Anti-infective agents and uses thereof

ABSTRACT

This invention relates to: (a) compounds and salts thereof that, inter alia, inhibit HCV; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application claims priority to U.S. Provisional PatentApplication No. 60/972,887 (filed Sep. 17, 2007) and U.S. ProvisionalPatent Application No. 61/096,794 (filed Sep. 13, 2008). The entire textof those applications is incorporated by reference into thisapplication.

FIELD OF THE INVENTION

This invention is directed to: (a) compounds and salts thereof that,inter alia, are useful as hepatitis C virus (HCV) inhibitors; (b)intermediates useful for the preparation of such compounds and salts;(c) compositions comprising such compounds and salts; (d) methods forpreparing such intermediates, compounds, salts, and compositions; (e)methods of use of such compounds, salts, and compositions; and (f) kitscomprising such compounds, salts, and compositions.

BACKGROUND OF THE INVENTION

Hepatitis C is a blood-borne, infectious, viral disease that is causedby a hepatotropic virus called HCV. At least six different HCV genotypes(with several subtypes within each genotype) are known to date. In NorthAmerica, HCV genotype 1a predominates, followed by HCV genotypes 1b, 2a,2b, and 3a. In the United States, HCV genotypes 1, 2, and 3 are the mostcommon, with about 80% of the hepatitis C patients having HCVgenotype 1. In Europe, HCV genotype 1b is predominant, followed by HCVgenotypes 2a, 2b, 2c, and 3a. HCV genotypes 4 and 5 are found almostexclusively in Africa. As discussed below, the patient's HCV genotype isclinically important in determining the patient's potential response totherapy and the required duration of such therapy.

An HCV infection can cause liver inflammation (hepatitis) that is oftenasymptomatic, but ensuing chronic hepatitis can result in cirrhosis ofthe liver (fibrotic scarring of the liver), liver cancer, and/or liverfailure. The World Health Organization estimates that about 170 millionpersons worldwide are chronically infected with HCV, and from aboutthree to about four million persons are newly infected globally eachyear. According to the Centers for Disease Control and Prevention, aboutfour million people in the United States are infected with HCV.Co-infection with the human immunodeficiency virus (HIV) is common, andrates of HCV infection among HIV positive populations are higher.

There is a small chance of clearing the virus spontaneously, but themajority of patients with chronic hepatitis C will not clear it withouttreatment. Indications for treatment typically include proven HCVinfection and persistent abnormal liver function tests. There are twotreatment regimens that are primarily used to treat hepatitis C:monotherapy (using an interferon agent—either a “conventional” orlonger-acting pegylated interferon) and combination therapy (using aninterferon agent and ribavirin). Interferon, which is injected into thebloodstream, works by bolstering the immune response to HCV; andribavirin, which is taken orally, is believed to work by preventing HCVreplication. Taken alone, ribavirin does not effectively suppress HCVlevels, but an interferon/ribavirin combination is more effective thaninterferon alone. Typically, hepatitis C is treated with a combinationof pegylated interferon alpha and ribavirin for a period of 24 or 48weeks, depending on the HCV genotype.

The goal of treatment is sustained viral response—meaning that HCV isnot measurable in the blood after therapy is completed. Followingtreatment with a combination of pegylated interferon alpha andribavirin, sustained cure rates (sustained viral response) of about 75%or better occur in people with HCV genotypes 2 and 3 in 24 weeks oftreatment, about 50% in those with HCV genotype 1 with 48 weeks oftreatment, and about 65% in those with HCV genotype 4 in 48 weeks oftreatment.

Treatment may be physically demanding, particularly for those with priorhistory of drug or alcohol abuse, because both interferon and ribavirinhave numerous side effects. Common interferon-associated side effectsinclude flu-like symptoms, extreme fatigue, nausea, loss of appetite,thyroid problems, high blood sugar, hair loss, and skin reactions at theinjection site. Possible serious interferon-associated side effectsinclude psychoses (e.g., suicidal behavior), heart problems (e.g., heartattack, low blood pressure), other internal organ damage, blood problems(e.g., blood counts falling dangerously low), and new or worseningautoimmune disease (e.g., rheumatoid arthritis). Ribavirin-associatedside effects include anemia, fatigue, irritability, skin rash, nasalstuffiness, sinusitis, and cough. Ribavirin can also cause birthdefects, so pregnancy in female patients and female partners of malepatients must be avoided during treatment and for six months afterward.

Some patients do not complete treatment because of the serious sideeffects discussed above; other patients (non-responders) continue tohave measurable HCV levels despite treatment; and yet other patients(relapsers) “clear” the virus during therapy, but the virus returnssometime after completion of the treatment regimen. Thus, therecontinues to be a need for alternative compounds, compositions, andmethods of treatment (used either in combination with or in lieu of aninterferon agent and/or ribavirin) to alleviate the symptoms ofhepatitis C, thereby providing partial or complete relief. Thisinvention provides compounds (including salts thereof), compositions,and methods of treatment that generally address such a need.

SUMMARY OF THE INVENTION

This invention is directed to compounds that correspond in structure toformula I:

In formula I:

is selected from the group consisting of single carbon-carbon bond anddouble carbon-carbon bond;

R¹ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group;

R² is selected from the group consisting of hydrogen, halo, hydroxy,methyl, cyclopropyl, and cyclobutyl;

R³ is selected from the group consisting of hydrogen, halo, oxo, andmethyl;

R⁴ is selected from the group consisting of halo, alkyl, alkenyl,alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino,aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, andheterocyclyl, wherein:

-   -   (a) the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, and            alkylsulfonyl, or        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl, and    -   (b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,        alkynyloxy, and alkylsulfonyl, optionally are substituted with        one or more substituents independently selected from the group        consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino,        alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl,        wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl, and    -   (c) the carbocyclyl and heterocyclyl optionally are substituted        with up to three substituents independently selected from the        group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro,        cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl,        carbocyclyl, and heterocyclyl, wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl;

R⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl,alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy,carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo;

L is selected from the group consisting of C(R^(A))═C(R^(B)), ethylene,and cyclopropyl-1,2-ene;

R^(A) and R^(B) are independently selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl, and halo,wherein:

-   -   the C₁-C₆-alkyl optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, halo, hydroxy, nitro, oxo, amino, cyano,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and        heterocyclyl;

R⁶ is selected from the group consisting of C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl, wherein each such substituent optionally is substitutedwith one or more substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K);

each R^(E) is independently selected from the group consisting of halo,nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydro,wherein:

-   -   the amino optionally is substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkenyl, and alkynyl;

each R^(F) is independently selected from the group consisting of alkyl,alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo,        aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,        wherein:        -   the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl,            and heterocyclyl optionally are substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,            alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino,            hydroxy, and alkyloxy, wherein:            -   amino portion of the alkylsulfonylamino optionally is                substituted with a substituent selected from the group                consisting of alkyl, alkenyl, and alkynyl;

each R^(G) is independently selected from the group consisting ofcarbocyclyl and heterocyclyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro,        azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,        alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,        alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy,        carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl;

each R^(H) is independently selected from the group consisting ofalkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy,and alkynylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl;

each R^(I) is independently selected from the group consisting ofalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl,alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl,wherein:

-   -   (a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl,        heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:        -   the carbocyclyl and heterocyclyl optionally are substituted            with one or two substituents independently selected from the            group consisting of halo, alkyl, and oxo;

each R^(J) is independently selected from the group consisting ofcarbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino,alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino,alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino,alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,alkyloxycarbonylaminoimino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,        alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or more substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy,            halo, nitro, cyano, azido, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or more substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,            and alkynyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy,        alkynyloxy, halo, nitro, cyano, azido, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, and alkynyl; and

each R^(K) is independently selected from the group consisting ofaminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl,wherein:

-   -   (a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl; and    -   (b) the aminosulfonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, and alkynyl.

This invention also is directed to the salts (including pharmaceuticallyacceptable salts) of the compounds of the invention.

This invention also is directed to compositions (includingpharmaceutical compositions) that comprise one or more compounds and/orsalts of the invention, and, optionally, one or more additionaltherapeutic agents.

This invention also is directed to kits that comprise one or morecompounds and/or salts of the invention, and, optionally, one or moreadditional therapeutic agents.

This invention also is directed to methods of use of the compounds,salts, compositions, and/or kits of the invention to, for example,inhibit replication of an RNA virus (including HCV), treat a diseasetreatable by inhibiting HCV ribonucleic acid (RNA) polymerase (includinghepatitis C).

This invention also is directed to a use of one or more compounds and/orsalts of the invention to prepare a medicament. The medicamentoptionally can comprise one or more additional therapeutic agents. Insome embodiments, the medicament is useful for treating hepatitis C.

Further benefits of Applicants' invention will be apparent to oneskilled in the art from reading this patent application.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an illustrative PXRD pattern for the disodium saltnonahydrate of compound IB-L1-1.1.

FIG. 2 shows an illustrative PXRD pattern for the disodium salttetrahydrate of compound IB-L1-1.1.

FIG. 3 shows an illustrative TGA profile of the disodium salttetrahydrate of compound IB-L1-1.1.

FIG. 4 shows an illustrative PXRD pattern for the dipotassium salttetrahydrate of compound IB-L1-1.1.

FIG. 5 shows an illustrative PXRD pattern for the monopotassium salttrihydrate of compound IB-L1-1.1.

FIG. 6 shows an illustrative PXRD pattern for the monopotassium saltdihydrate of compound IB-L1-1.1.

FIG. 7 shows an illustrative TGA profile of the monopotassium saltdihydrate of compound IB-L1-1.1.

FIG. 8 shows an illustrative PXRD pattern for the 1/7 potassium salt ofcompound IB-L1-1.1.

FIG. 9 shows an illustrative PXRD pattern for the monodiethylamine salttetrahydrate of compound IB-L1-1.1.

FIG. 10 shows an illustrative TGA profile of the monodiethylamine salttetrahydrate of compound IB-L1-1.1.

FIG. 11 shows an illustrative PXRD pattern for the pattern A polymorphof compound IB-L1-1.1.

FIG. 12 shows an illustrative DSC profile of the pattern A polymorph ofcompound IB-L1-1.1.

FIG. 13 shows an illustrative PXRD pattern for the pattern B polymorphof compound IB-L1-1.1.

FIG. 14 shows an illustrative PXRD pattern for the pattern C polymorphof compound IB-L1-1.1.

FIG. 15 shows an illustrative PXRD pattern for the pattern D polymorphof compound IB-L1-1.1.

FIG. 16 shows an illustrative PXRD pattern for the pattern A hydrate ofcompound IB-L1-1.1.

FIG. 17 shows an illustrative TGA profile of the pattern A hydrate ofcompound IB-L1-1.1.

FIG. 18 shows an illustrative PXRD pattern for the pattern B hydrate ofcompound IB-L1-1.1.

FIG. 19 shows an illustrative TGA profile of the pattern B hydrate ofcompound IB-L1-1.1.

FIG. 20 shows an illustrative PXRD pattern for the pattern C hydrate ofcompound IB-L1-1.1.

FIG. 21 shows an illustrative TGA profile of the pattern C hydrate ofcompound IB-L1-1.1.

FIG. 22 shows an illustrative PXRD pattern for the pattern D hydrate ofcompound IB-L1-1.1.

FIG. 23 shows an illustrative PXRD pattern for the pattern E hydrate ofcompound IB-L1-1.1.

DETAILED DESCRIPTION OF THE INVENTION

This detailed description is intended only to acquaint others skilled inthe art with Applicants' invention, its principles, and its practicalapplication so that others skilled in the art may adapt and apply theinvention in its numerous forms, as they may be best suited to therequirements of a particular use. This description and its specificexamples are intended for purposes of illustration only. This invention,therefore, is not limited to the embodiments described in this patentapplication, and may be variously modified.

A. Definitions

The term “alkyl” (alone or in combination with another term(s)) means astraight- or branched-chain saturated hydrocarbyl substituent typicallycontaining from 1 to about 20 carbon atoms, more typically from 1 toabout 8 carbon atoms, and even more typically from 1 to about 6 carbonatoms. Examples of such substituents include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,and hexyl. As in this definition, throughout this detailed descriptionApplicants have provided illustrative examples. The provision of suchillustrative examples should not be interpreted as if the providedillustrative examples are the only options available to one skilled inthe art.

The term “alkenyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore double bonds and typically from 2 to about 20 carbon atoms, moretypically from about 2 to about 8 carbon atoms, and even more typicallyfrom about 2 to about 6 carbon atoms. Examples of such substituentsinclude ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl,1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.

The term “alkynyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore triple bonds and typically from 2 to about 20 carbon atoms, moretypically from about 2 to about 8 carbon atoms, and even more typicallyfrom about 2 to about 6 carbon atoms. Examples of such substituentsinclude ethynyl, 2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl.

The term “carbocyclyl” (alone or in combination with another term(s))means a saturated cyclic (i.e., “cycloalkyl”), partially saturatedcyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”)hydrocarbyl substituent containing from 3 to 14 carbon ring atoms (“ringatoms” are the atoms bound together to form the ring or rings of acyclic substituent). A carbocyclyl may be a single ring, which typicallycontains from 3 to 6 ring atoms. Examples of such single-ringcarbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl(cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl,cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl,cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3rings fused together, such as naphthalenyl, tetrahydronaphthalenyl(tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl,phenanthrenyl, and decalinyl.

The term “cycloalkyl” (alone or in combination with another term(s))means a saturated cyclic hydrocarbyl substituent containing from 3 to 14carbon ring atoms. A cycloalkyl may be a single carbon ring, whichtypically contains from 3 to 6 carbon ring atoms. Examples ofsingle-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl. A cycloalkyl alternatively may be 2 or 3 carbon ringsfused together, such as, decalinyl.

The term “aryl” (alone or in combination with another term(s)) means anaromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examplesof aryls include phenyl, naphthalenyl, and indenyl.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicatedby the prefix “C_(x)-C_(y)-” wherein x is the minimum and y is themaximum number of carbon atoms in the substituent. Thus, for example,“C₁-C₆-alkyl” refers to an alkyl substituent containing from 1 to 6carbon atoms. Illustrating further, C₃-C₆-cycloalkyl means a saturatedhydrocarbyl ring containing from 3 to 6 carbon ring atoms.

The term “hydrogen” (alone or in combination with another term(s)) meansa hydrogen radical, and may be depicted as —H.

The term “hydroxy” (alone or in combination with another term(s)) means—OH.

The term “nitro” (alone or in combination with another term(s)) means—NO₂.

The term “cyano” (alone or in combination with another term(s)) means—CN, which also may be depicted as —C≡N.

The term “keto” (alone or in combination with another term(s)) means anoxo radical, and may be depicted as ═O.

The term “carboxy” (alone or in combination with another term(s)) means—C(O)—OH.

The term “amino” (alone or in combination with another term(s)) means—NH₂.

The term “imino” (alone or in combination with another term(s)) means═NH.

The term “aminoimino” (alone or in combination with another term(s))means ═NNH₂.

The term “halogen” or “halo” (alone or in combination with anotherterm(s)) means a fluorine radical (which may be depicted as —F),chlorine radical (which may be depicted as —Cl), bromine radical (whichmay be depicted as —Br), or iodine radical (which may be depicted as—I).

A substituent is “substitutable” if it comprises at least one carbon ornitrogen atom that is bonded to one or more hydrogen atoms. Thus, forexample, hydrogen, halogen, and cyano do not fall within thisdefinition. In addition, a sulfur atom in a heterocyclyl containing suchatom is substitutable with one or two oxo substituents.

If a substituent is described as being “substituted”, a non-hydrogenradical is in the place of hydrogen radical on a carbon or nitrogen ofthe substituent. Thus, for example, a substituted alkyl substituent isan alkyl substituent in which at least one non-hydrogen radical is inthe place of a hydrogen radical on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro radical, anddifluoroalkyl is alkyl substituted with two fluoro radicals. It shouldbe recognized that if there are more than one substitution on asubstituent, each non-hydrogen radical may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) not substituted or (2) substituted. If asubstituent is described as being optionally substituted with up to aparticular number of non-hydrogen radicals, that substituent may beeither (1) not substituted; or (2) substituted by up to that particularnumber of non-hydrogen radicals or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen radicals, then any heteroaryl withless than 3 substitutable positions would be optionally substituted byup to only as many non-hydrogen radicals as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen radical. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogenradicals, then a primary amino nitrogen will be optionally substitutedwith up to 2 non-hydrogen radicals, whereas a secondary amino nitrogenwill be optionally substituted with up to only 1 non-hydrogen radical.

This patent application uses the terms “substituent” and “radical”interchangeably.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl substituent in which atleast one hydrogen radical is replaced with a halogen radical. Examplesof haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should berecognized that if a substituent is substituted by more than one halogenradical, those halogen radicals may be identical or different (unlessotherwise stated).

The prefix “perhalo” indicates that every hydrogen radical on thesubstituent to which the prefix is attached is replaced withindependently selected halogen radicals, i.e., each hydrogen radical onthe substituent is replaced with a halogen radical. If all the halogenradicals are identical, the prefix typically will identify the halogenradical. Thus, for example, the term “perfluoro” means that everyhydrogen radical on the substituent to which the prefix is attached issubstituted with a fluorine radical. To illustrate, the term“perfluoroalkyl” means an alkyl substituent wherein a fluorine radicalis in the place of each hydrogen radical.

The term “carbonyl” (alone or in combination with another term(s)) means—C(O)—.

The term “aminocarbonyl” (alone or in combination with another term(s))means —C(O)—NH₂.

The term “oxy” (alone or in combination with another term(s)) means anether substituent, and may be depicted as —O—.

The term “alkoxy” (alone or in combination with another term(s)) meansan alkylether substituent, i.e., —O-alkyl. Examples of such asubstituent include methoxy (—O—CH₃), ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

The term “alkylcarbonyl” (alone or in combination with another term(s))means —C(O)-alkyl.

The term “aminoalkylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-alkyl-NH₂.

The term “alkoxycarbonyl” (alone or in combination with another term(s))means —C(O)—O-alkyl.

The term “carbocyclylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-carbocyclyl.

Similarly, the term “heterocyclylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-heterocyclyl.

The term “carbocyclylalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-carbocyclyl.

Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combinationwith another term(s)) means —C(O)-alkyl-heterocyclyl.

The term “carbocyclyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-carbocyclyl.

The term “carbocyclylalkoxycarbonyl” (alone or in combination withanother term(s)) means —C(O)—O-alkyl-carbocyclyl.

The term “thio” or “thia” (alone or in combination with another term(s))means a thiaether substituent, i.e., an ether substituent wherein adivalent sulfur atom is in the place of the ether oxygen atom. Such asubstituent may be depicted as —S—. This, for example,“alkyl-thio-alkyl” means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).

The term “thiol” or “sulfhydryl” (alone or in combination with anotherterm(s)) means a sulfhydryl substituent, and may be depicted as —SH.

The term “(thiocarbonyl)” (alone or in combination with another term(s))means a carbonyl wherein the oxygen atom has been replaced with asulfur. Such a substituent may be depicted as —C(S)—.

The term “sulfonyl” (alone or in combination with another term(s)) means—S(O)₂—.

The term “aminosulfonyl” (alone or in combination with another term(s))means —S(O)₂—NH₂.

The term “sulfinyl” or “sulfoxido” (alone or in combination with anotherterm(s)) means —S(O)—.

The term “heterocyclyl” (alone or in combination with another term(s))means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e.,“heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”)ring structure containing a total of 3 to 14 ring atoms. At least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl(thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl,oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl,thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl,thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl),oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl,tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl(including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), orpyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl (including1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl(including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)), oxathiazinyl(including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl,or 1,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl,1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)),morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

A heterocyclyl alternatively may be 2 or 3 rings fused together, suchas, for example, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl,naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.Other examples of fused-ring heterocyclyls include benzo-fusedheterocyclyls, such as indolyl, isoindolyl (isobenzazolyl,pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl(benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) orisoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl(1,3-benzodiazinyl)), benzopyranyl (including chromanyl orisochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl,1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), andbenzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl).

The term “2-fused ring” heterocyclyl (alone or in combination withanother term(s)) means a saturated, partially saturated, or arylheterocyclyl containing 2 fused rings. Examples of 2-fused-ringheterocyclyls include indolizinyl, quinolizinyl, purinyl,naphthyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl,isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl,benzopyranyl, benzothiopyranyl, benzoxazolyl, anthranilyl,benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl,isobenzofuranyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl,benzotriazolyl, benzoxazinyl, and tetrahydroisoquinolinyl.

The term “heteroaryl” (alone or in combination with another term(s))means an aromatic heterocyclyl containing from 5 to 14 ring atoms. Aheteroaryl may be a single ring or 2 or 3 fused rings. Examples ofheteroaryl substituents include 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or1,2,3-triazinyl; 5-membered ring substituents such as imidazyl, furanyl,thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-,1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ringsubstituents such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl, and anthranilyl; and 6/6-membered fused rings such asbenzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, andbenzoxazinyl.

A prefix attached to a multi-component substituent only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆-prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkoxyalkyl indicates that only the alkoxy component ofthe alkoxyalkyl substituent is substituted with one or more halogenradicals. If halogen substitution may alternatively or additionallyoccur on the alkyl component, the substituent would instead be describedas “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” Andfinally, if the halogen substitution may only occur on the alkylcomponent, the substituent would instead be described as“alkoxyhaloalkyl.”

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

When words are used to describe a substituent, the rightmost-describedcomponent of the substituent is the component that has the free valence.

When a chemical formula is used to describe a substituent, the dash onthe left side of the formula indicates the portion of the substituentthat has the free valence.

When a chemical formula is used to describe a linking element betweentwo other elements of a depicted chemical structure, the leftmost dashof the substituent indicates the portion of the substituent that isbound to the left element in the depicted structure. The rightmost dash,on the other hand, indicates the portion of the substituent that isbound to the right element in the depicted structure. To illustrate, ifthe depicted chemical structure is X-L-Y and L is described as—C(O)—N(H)—, then the chemical would be X—C(O)—N(H)—Y.

With reference to the use of the words “comprise” or “comprises” or“comprising” in this patent application (including the claims),Applicants note that unless the context requires otherwise, those wordsare used on the basis and clear understanding that they are to beinterpreted inclusively, rather than exclusively, and that Applicantsintend each of those words to be so interpreted in construing thispatent application, including the claims below.

ChemDraw software has been used to generate the compound names in thispatent application.

The term “amorphous” as applied to a compound refers to a solid-state inwhich the compound molecules are present in a disordered arrangement anddo not form a distinguishable crystal lattice or unit cell. Whensubjected to X-ray powder diffraction, an amorphous compound does notproduce any characteristic crystalline peaks.

The term “crystalline form” as applied to a compound refers to asolid-state in which the compound molecules are arranged to form adistinguishable crystal lattice (i) comprising distinguishable unitcells, and (ii) yielding diffraction pattern peaks when subjected toX-ray radiation.

The term “purity”, unless otherwise qualified, means the chemical purityof a compound according to conventional HPLC assay.

The term “phase purity” means the solid-state purity of a compound withregard to a particular crystalline or amorphous form of the compound asdetermined by X-ray powder diffraction analytical methods.

The term “phase pure” refers to purity with respect to other solid-stateforms of the compound, and does not necessarily imply a high degree ofchemical purity with respect to other compounds.

The term “PXRD” means X-ray powder diffraction.

The term “TGA” means thermogravimetric analysis.

The term “DSC” means differential scanning calorimetry.

B. Compounds

This invention is directed, in part, to compounds that are phenyl-uracilderivatives that correspond in structure to formula I:

In these compounds,

is selected from the group consisting of single carbon-carbon bond anddouble carbon-carbon bond.

In some embodiments,

is a single carbon-carbon bond. In these embodiments, the compounds offormula I correspond in structure to the following formula (i.e.,formula IA):

In other embodiments,

is a double carbon-carbon bond. In these embodiments, the compounds offormula I correspond in structure to the following formula (i.e.,formula IB):

B1. Substituent R¹

R¹ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R¹ is hydrogen.

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R¹ is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula I. Nitrogen-protecting groupssuitable for preparing compounds of formula I are known to those skilledin the art.

B2. Substituent R²

R² is selected from the group consisting of hydrogen, halo, hydroxy,methyl, cyclopropyl, and cyclobutyl.

In some embodiments, R² is hydrogen.

In some embodiments, R² is halo. In some such embodiments, R² isselected from the group consisting of fluoro and chloro. In other suchembodiments, R² is fluoro. In yet other such embodiments, R² is chloro.In yet other such embodiments, R² is bromo. In further such embodiments,R² is iodo.

In some embodiments, R² is hydroxy.

In some embodiments, R² is methyl.

In some embodiments, R² is cyclopropyl.

In some embodiments, R² is cyclobutyl.

In some embodiments, R² is selected from the group consisting ofhydrogen, methyl, hydroxy, and halo. In some such embodiments, R² isselected from the group consisting of hydrogen, methyl, hydroxy, fluoro,and chloro. In other such embodiments, R² is selected from the groupconsisting of hydrogen, methyl, hydroxy, and fluoro. In yet other suchembodiments, R² is selected from the group consisting of hydrogen,methyl, hydroxy, and chloro. In yet other such embodiments, R² isselected from the group consisting of hydrogen, methyl, hydroxy, andbromo. In further such embodiments, R² is selected from the groupconsisting of hydrogen, methyl, hydroxy, and iodo.

In some embodiments, R² is selected from the group consisting ofhydrogen, methyl, and halo. In some such embodiments, R² is selectedfrom the group consisting of hydrogen, methyl, fluoro, and chloro. Inother such embodiments, R² is selected from the group consisting ofhydrogen, methyl, and fluoro. In yet other such embodiments, R² isselected from the group consisting of hydrogen, methyl, and chloro. Inyet other such embodiments, R² is selected from the group consisting ofhydrogen, methyl, and bromo. In further such embodiments, R² is selectedfrom the group consisting of hydrogen, methyl, and iodo.

In some embodiments, R² is selected from the group consisting ofhydrogen and halo. In some such embodiments, R² is selected from thegroup consisting of hydrogen, fluoro, and chloro. In other suchembodiments, R² is selected from the group consisting of hydrogen andfluoro. In yet other such embodiments, R² is selected from the groupconsisting of hydrogen and chloro. In yet other such embodiments, R² isselected from the group consisting of hydrogen and bromo. In furthersuch embodiments, R² is selected from the group consisting of hydrogenand iodo.

B3. Substituent R³

R³ is selected from the group consisting of hydrogen, halo, oxo, andmethyl. In some such embodiments, R³ is selected from the groupconsisting of hydrogen, fluoro, oxo, and methyl. In other suchembodiments, R³ is selected from the group consisting of hydrogen,chloro, oxo, and methyl. In yet other such embodiments, R³ is selectedfrom the group consisting of hydrogen, bromo, oxo, and methyl. In yetother such embodiments, R³ is selected from the group consisting ofhydrogen, iodo, oxo, and methyl.

In some embodiments, R³ is selected from the group consisting ofhydrogen, halo, and oxo. In some such embodiments, R³ is selected fromthe group consisting of hydrogen, fluoro, and oxo. In other suchembodiments, R³ is selected from the group consisting of hydrogen,chloro, and oxo. In yet other such embodiments, R³ is selected from thegroup consisting of hydrogen, bromo, and oxo. In yet other suchembodiments, R³ is selected from the group consisting of hydrogen, iodo,and oxo.

In some embodiments, R³ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R³ is hydrogen.

In some embodiments, R³ is methyl.

In some embodiments, R³ is oxo.

In some embodiments, R³ is halo. In some such embodiments, R³ is fluoro.In other such embodiments, R³ is chloro. In yet other such embodiments,R³ is bromo. In further such embodiments, R³ is iodo.

B4. Substituent R⁴

R⁴ is selected from the group consisting of halo, alkyl, alkenyl,alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino,aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, andheterocyclyl, wherein:

-   -   (a) the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, and            alkylsulfonyl, or        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl,    -   (b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,        alkynyloxy, and alkylsulfonyl, optionally are substituted with        one or more substituents independently selected from the group        consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino,        alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl,        wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl, and    -   (c) the carbocyclyl and heterocyclyl optionally are substituted        with up to three substituents independently selected from the        group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro,        cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl,        carbocyclyl, and heterocyclyl, wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, and            alkylsulfonyl, or        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,        and alkylsulfonyl, optionally are substituted with one or more        substituents independently selected from the group consisting of        halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy,        trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   the carbocyclyl and heterocyclyl optionally are substituted with        up to three substituents independently selected from the group        consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano,        azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl,        and heterocyclyl, wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   (a) the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, and alkynyl, or,        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl; and    -   (b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,        alkynyloxy, alkylsulfonyl, carbocyclyl, and heterocyclyl        optionally are substituted with up to three substituents        independently selected from the group consisting of halo, oxo,        nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and        heterocyclyl, wherein the amino optionally is substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl,            alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,            carbocyclylalkyl, and heterocyclylalkyl, or,        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

the amino, aminocarbonyl, and aminosulfonyl optionally are substitutedwith:

-   -   (1) one or two substituents independently selected from the        group consisting of alkyl, alkenyl, and alkynyl, or,    -   (2) two substituents that, together with the amino nitrogen,        form a single-ring heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,alkylsulfonyl, carbocyclyl, and heterocyclyl optionally are substitutedwith up to three substituents independently selected from the groupconsisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy,carbocyclyl, and heterocyclyl, wherein the amino optionally issubstituted with:

-   -   (1) one or two substituents independently selected from the        group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl,        alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,        carbocyclylalkyl, and heterocyclylalkyl, or,    -   (2) two substituents that, together with the amino nitrogen,        form a single-ring heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the amino optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, and alkylsulfonyl,    -   (b) the C₁-C₄-alkyl, C₂-C₄-alkenyl, and C₂-C₄-alkynyl optionally        are substituted with one or more substituents independently        selected from the group consisting of halo, oxo, hydroxy,        alkyloxy, and trimethylsilyl, and    -   (c) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with up to three substituents        independently selected from the group consisting of alkyl,        alkenyl, alkynyl, halo, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.

In some embodiments, R⁴ is selected from the group consisting ofC₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the amino optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, and alkylsulfonyl,    -   (b) the C₁-C₄-alkyl, C₂-C₄-alkenyl, and C₂-C₄-alkynyl optionally        are substituted with one or more substituents independently        selected from the group consisting of halo, oxo, hydroxy,        alkyloxy, and trimethylsilyl, and    -   (c) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with up to three substituents        independently selected from the group consisting of alkyl,        alkenyl, alkynyl, halo, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.

In some embodiments, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

(a) the C₁-C₄-alkyl optionally is substituted with up to threesubstituents independently selected from the group consisting of halo,oxo, hydroxy, alkyloxy, and trimethylsilyl, and

(b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally aresubstituted with one or two substituents independently selected from thegroup consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with one or two        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and    -   (b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with a substituent selected from the        group consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R⁴ is selected from the group consisting ofC₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with up to three        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and    -   (b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl, halo,        and alkylsulfonylamino.

In some embodiments, R⁴ is selected from the group consisting of halo,tert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally        are substituted with a substituent selected from the group        consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R⁴ is selected from the group consisting oftert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally        are substituted with a substituent selected from the group        consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, alkyloxyalkyl,trimethylsilylalkynyl, alkylcarbocyclyl, carbocyclyl, alkylheterocyclyl,heterocyclyl, halocarbocyclyl, alkylsulfonylamino, and alkylsulfonyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl.

In some embodiments, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl.

In some such embodiment, R⁴ is selected from the group consisting ofhalo, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino,C₁-C₄-alkylsulfonyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. Inother such embodiment, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,phenyl, and 5-6-membered heteroaryl.

In some embodiments, R⁴ is selected from the group consisting ofC₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In some suchembodiment, R⁴ is selected from the group consisting of C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₆-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiment,R⁴ is selected from the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, phenyl, and 5-6-memberedheteroaryl.

In some embodiments, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In othersuch embodiments, R⁴ is selected from the group consisting of halo,C₁-C₄-alkyl, phenyl, and 5-6-membered heteroaryl.

In some embodiments, R⁴ is selected from the group consisting ofC₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R⁴ is selected from the group consisting ofC₁-C₄-alkyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In othersuch embodiments, R⁴ is selected from the group consisting ofC₁-C₄-alkyl, phenyl, and 5-6-membered heteroaryl.

In some embodiments, R⁴ is selected from the group consisting of halo,tert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R⁴ is selected from the group consisting of halo,tert-butyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In other suchembodiments, R⁴ is selected from the group consisting of halo,tert-butyl, phenyl, and 5-6-membered heteroaryl.

In some embodiments, R⁴ is selected from the group consisting oftert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R⁴ is selected from the group consisting oftert-butyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In other suchembodiments, R⁴ is selected from the group consisting of tert-butyl,phenyl, and 5-6-membered heteroaryl.

In some embodiments, R⁴ is selected from the group consisting ofC₃-C₆-carbocyclyl and 5-6-membered heterocyclyl. In some suchembodiments, R⁴ is selected from the group consisting of C₆-carbocyclyl,and 5-6-membered heterocyclyl. In other such embodiments, R⁴ is selectedfrom the group consisting of phenyl and 5-6-membered heteroaryl.

Suitable carbocyclyls for the above embodiments include, for example,cyclopropyl and phenyl.

Suitable heterocyclyls for the above embodiments include, for example,furanyl, thienyl, and pyridinyl.

In some embodiments, R⁴ is selected from the group consisting of halo,alkyl, and alkyloxy.

In some embodiments, R⁴ is alkyl.

In some embodiments, R⁴ is tert-butyl.

B5. Substituent R⁵

R⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl,alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy,carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo.

In some embodiments, R⁵ is selected from the group consisting ofhydrogen, hydroxy, alkyloxy, and halo. In some such embodiments, R⁵ isselected from the group consisting of hydrogen, hydroxy, alkyloxy, andfluoro. In other such embodiments, R⁵ is selected from the groupconsisting of hydrogen, hydroxy, alkyloxy, and fluoro. In yet other suchembodiments, R⁵ is selected from the group consisting of hydrogen,hydroxy, alkyloxy, and chloro. In yet other such embodiments, R⁵ isselected from the group consisting of hydrogen, hydroxy, alkyloxy, andbromo. In further such embodiments, R⁵ is selected from the groupconsisting of hydrogen, hydroxy, alkyloxy, and iodo.

In some embodiments, R⁵ is selected from the group consisting ofhydrogen, hydroxy, methoxy, and halo. In some such embodiments, R⁵ isselected from the group consisting of hydrogen, hydroxy, methoxy, andfluoro. In other such embodiments, R⁵ is selected from the groupconsisting of hydrogen, hydroxy, methoxy, and chloro. In yet other suchembodiments, R⁵ is selected from the group consisting of hydrogen,hydroxy, methoxy, and bromo. In further such embodiments, R⁵ is selectedfrom the group consisting of hydrogen, hydroxy, methoxy, and iodo.

In some embodiments, R⁵ is selected from the group consisting ofhydrogen, hydroxy, and alkyloxy. In some such embodiments, R⁵ isselected from the group consisting of hydrogen, hydroxy, methoxy, andethoxy.

In some embodiments, R⁵ is s hydrogen.

In some embodiments, R⁵ is hydroxy.

In some embodiments, R⁵ is alkyloxy.

In some embodiments, R⁵ is methoxy.

In some embodiments, R⁵ is ethoxy.

B6Substituent L

L is selected from the group consisting of C(R^(A))═C(R^(B)), ethylene,and cyclopropyl-1,2-ene, wherein R^(A) and R^(B) are as discussed below.

In some embodiments, L is C(R^(A))═C(R^(B)), wherein R^(A) and R^(B) areas discussed below. In these embodiments, the compounds of formula Icorrespond in structure to formula I-L1:

In some such embodiments, the compounds correspond in structure toformula IA-L1:

In other such embodiments, the compounds correspond in structure toformula IB-L1:

Typically, the compounds of formula I-L1 are more potent if R⁶ and thephenyl-uracil are on opposite sides of the double bond (i.e., in transconfiguration in relation to the double bond).

In some embodiments, L is ethylene. In these embodiments, the compoundsof formula I correspond in structure to I-L5-2:

In some such embodiments, the compounds correspond in structure toformula IA-L5-2:

In other such embodiments, the compounds correspond in structure toformula IB-L5-2:

In some embodiments, L is cyclopropyl-1,2-ene. In these embodiments, thecompounds of formula I correspond in structure to formula I-L8:

In some such embodiments, the compounds correspond in structure toformula IA-L8:

In other such embodiments, the compounds correspond in structure toformula IB-L8:

B 7. Substituents R^(A) and R^(B)

R^(A) and R^(B) are independently selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl, and halo,wherein:

-   -   the C₁-C₆-alkyl optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, halo, hydroxy, nitro, oxo, amino, cyano,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and        heterocyclyl.

In some embodiments, one of R^(A) and R^(B) is hydrogen, and the otheris selected from the group consisting of C₁-C₆-alkyl, C₁-C₆-alkyloxy,C₃-C₈-cycloalkyl, and halo, wherein:

-   -   the C₁-C₆-alkyl optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, halo, hydroxy, nitro, oxo, amino, cyano,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and        heterocyclyl.

In some embodiments, R^(A) and R^(B) are independently selected from thegroup consisting of hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy,C₃-C₈-cycloalkyl, and halo.

In some of the above embodiments, R^(A) is hydrogen. In other of theabove embodiments, R^(B) is hydrogen.

In some embodiment, one of R^(A) and R^(B) is hydrogen, and the other isselected from the group consisting of hydrogen, methyl, methoxy, andhalo.

In some embodiments, R^(A) is hydrogen, and R^(B) is selected from thegroup consisting of methyl, methoxy, and halo. In some such embodiments,R^(B) is selected from the group consisting of methyl, methoxy, andfluoro. In other such embodiments, R^(B) is selected from the groupconsisting of methyl, methoxy, and chloro. In yet other suchembodiments, R^(B) is selected from the group consisting of methyl,methoxy, and bromo. In further such embodiments, R^(B) is selected fromthe group consisting of methyl, methoxy, and iodo. In yet further suchembodiments, R^(B) is selected from the group consisting of methyl,methoxy, chloro, and fluoro.

In some embodiments, R^(B) is hydrogen, and R^(A) is selected from thegroup consisting of methyl, methoxy, and halo. In some such embodiments,R^(A) is selected from the group consisting of methyl, methoxy, andfluoro. In other such embodiments, R^(A) is selected from the groupconsisting of methyl, methoxy, and chloro. In yet other suchembodiments, R^(A) is selected from the group consisting of methyl,methoxy, and bromo. In further such embodiments, R^(A) is selected fromthe group consisting of methyl, methoxy, and iodo. In yet further suchembodiments, R^(A) is selected from the group consisting of methyl,methoxy, chloro, and fluoro.

In some embodiments, R^(A) is hydrogen, and R^(B) is hydrogen.

B8. Substituent R⁶

R⁶ is selected from the group consisting of C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl, wherein each such substituent optionally is substitutedwith one or more substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K),wherein R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K) are asdescribed below. In some such embodiments,

the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ringcarbocyclyl, and fused 2-ring heterocyclyl are not substituted. In othersuch embodiments, the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl,fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substitutedwith a substituent selected from the group consisting of R^(E), R^(F),R^(G), R^(H), R^(I), R^(J), and R^(K). In other such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with a substituentselected from the group consisting of R^(E), R^(F), R^(I), R^(J), andR^(K). In other such embodiments, the C₅-C₆-carbocyclyl, 5-6-memberedheterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclylare substituted with a substituent selected from the group consisting ofR^(E), R^(F), and R^(J). In other such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with a substituentselected from the group consisting of R^(F) and R^(J). In other suchembodiments, the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted withR^(J). In yet other such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In yet other such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(I), R^(J), andR^(K). In yet other such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), and R^(J). In yetother such embodiments, the C₅-C₆-carbocyclyl, 5-6-memberedheterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclylare substituted with two substituents independently selected from thegroup consisting of R^(F) and R^(J). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(I),R^(J), and R^(K). In further such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with three substituents independentlyselected from the group consisting of R^(E), R^(F), and R^(J). Infurther such embodiments, the C₅-C₆-carbocyclyl, 5-6-memberedheterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclylare substituted with three substituents independently selected from thegroup consisting of R^(F) and R^(J). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with one, two, or threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), R^(I), R^(J), and R^(K). In further suchembodiments, the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), and R^(J). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with one, two, or threesubstituents independently selected from the group consisting of R^(F)and R^(J).

In some embodiments, R⁶ is selected from the group consisting ofC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl, wherein each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In some such embodiments, theC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl are not substituted. Inother such embodiments, the C₅-C₆-carbocyclyl and 5-6-memberedheterocyclyl are substituted with a substituent selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). Inyet other such embodiments, the C₅-C₆-carbocyclyl and 5-6-memberedheterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In further such embodiments, the C₅-C₆-carbocyclyl and5-6-membered heterocyclyl are substituted with three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In further such embodiments, theC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl are substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁶ is C₅-C₆-carbocyclyl optionally substituted withone or more substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). Insome such embodiments, the C₅-C₆-carbocyclyl is not substituted. Inother such embodiments, the C₅-C₆-carbocyclyl is substituted with asubstituent selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In yet other such embodiments, theC₅-C₆-carbocyclyl is substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In further such embodiments, the C₅-C₆-carbocyclyl issubstituted with three substituents independently selected from thegroup consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).In further such embodiments, the C₅-C₆-carbocyclyl is substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁶ is 5-6-membered heterocyclyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), andR^(K). In some such embodiments, the 5-6-membered heterocyclyl is notsubstituted. In other such embodiments, the 5-6-membered heterocyclyl issubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In yet other suchembodiments, the 5-6-membered heterocyclyl is substituted with twosubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the 5-6-membered heterocyclyl is substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the 5-6-membered heterocyclyl is substituted with one, two,or three substituents independently selected from the group consistingof R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁶ is selected from the group consisting of fused2-ring carbocyclyl and fused 2-ring heterocyclyl, wherein each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In some such embodiments, the fused2-ring carbocyclyl and fused 2-ring heterocyclyl are not substituted. Inother such embodiments, the fused 2-ring carbocyclyl and fused 2-ringheterocyclyl are substituted with a substituent selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). Inyet other such embodiments, the fused 2-ring carbocyclyl and fused2-ring heterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In further such embodiments, the fused 2-ringcarbocyclyl and fused 2-ring heterocyclyl are substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring carbocyclyl and fused 2-ring heterocyclylare substituted with one, two, or three substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K).

In some embodiments, R⁶ is fused 2-ring carbocyclyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), andR^(K). In some such embodiments, the fused 2-ring carbocyclyl is notsubstituted. In other such embodiments, the fused 2-ring carbocyclyl issubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In yet other suchembodiments, the fused 2-ring carbocyclyl is substituted with twosubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring carbocyclyl is substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring carbocyclyl is substituted with one, two,or three substituents independently selected from the group consistingof R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁶ is fused 2-ring heterocyclyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), andR^(K). In some such embodiments, the fused 2-ring heterocyclyl is notsubstituted. In other such embodiments, the fused 2-ring heterocyclyl issubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In yet other suchembodiments, the fused 2-ring heterocyclyl is substituted with twosubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring heterocyclyl is substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring heterocyclyl is substituted with one, two,or three substituents independently selected from the group consistingof R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some of the above embodiments, the optionally substitutedC₅-C₆-carbocyclyl is selected from the group consisting of cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, and phenyl. In some such embodiments, the optionallysubstituted C₅-C₆-carbocyclyl is phenyl.

In some of the above embodiments, the optionally substitutedC₅-C₆-carbocyclyl is C₅-carbocyclyl. Examples of C₅-carbocyclyls includecyclopentyl, cyclopentenyl, and cyclopentadienyl.

In other of the above embodiments, the optionally substitutedC₅-C₆-carbocyclyl is C₆-carbocyclyl. Examples of C₆-carbocyclyls includecyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.

In some of the above embodiments, the optionally substituted5-6-membered-heterocyclyl is selected from the group consisting offuranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl),dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl,oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl,isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl,imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl,oxathiolanyl, triazolyl, oxadiazolyl, furazanyl, tetrazolyl,oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiazolidinyl,dihydrooxadiazolyl, dioxazolidinyl, pyranyl, dihydropyranyl,tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl,piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl,dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl,dihydrotriazinyl, tetrahydrotriazinyl, triazinanyl, oxazinyl,dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl,oxathiazinanyl, oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl,thiopyranyl, dihydrothiopyranyl, and tetrahydrothiopyranyl.

In some of the above embodiments, the optionally substituted5-6-membered-heterocyclyl is 5-membered heterocyclyl. Examples of such5-membered heterocyclyl include furanyl, dihydrofuranyl,tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl,tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl,dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl, oxazolidinyl,isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl, triazolyl,oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl, and dioxazolidinyl.

In other of the above embodiments, the optionally substituted5-6-membered-heterocyclyl is 6-membered heterocyclyl. Examples of6-membered heterocyclyls include pyranyl, dihydropyranyl,tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl,piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl,dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl,dihydrotriazinyl, tetrahydrotriazinyl, triazinanyl, oxazinyl,dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl,oxathiazinanyl, oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl,thiopyranyl, dihydrothiopyranyl, and tetrahydrothiopyranyl.

In some of the above embodiments, the optionally substituted fused2-ring carbocyclyl is selected from the group consisting ofnaphthalenyl, dihydronaphthalenyl, tetrahydronaphthalenyl,hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl,indenyl, dihydroindenyl, hexahydroindenyl, octahydroindenyl, pentalenyl,octahydropentalenyl, and hexahydropentalenyl. In some such embodiments,the optionally substituted fused 2-ring carbocyclyl is selected from thegroup consisting of naphthalenyl and dihydroindenyl. In some suchembodiments, the optionally substituted fused 2-ring carbocyclyl isnaphthalenyl. In other such embodiments, the optionally substitutedfused 2-ring carbocyclyl is dihydroindenyl. In further such embodiments,the optionally substituted fused 2-ring carbocyclyl is indenyl.

In some of the above embodiments, the optionally substituted fused2-ring heterocyclyl is selected from the group consisting of

X¹, X², and X³ are independently selected from the group consisting of Nand C(H);

X⁴ is selected from the group consisting of N(H), O, and S;

X⁵, X⁶, and X⁷ are independently selected from the group consisting of Nand C(H);

X⁸ is selected from the group consisting of N(H), O, and S;

X⁹ is selected from the group consisting of N(H), O, and S;

X¹⁰, X¹¹, X¹², and X¹³ are independently selected from the groupconsisting of N and C(H);

X¹⁴ is selected from the group consisting of N(H), O, and S;

X¹⁵, X¹⁶, X¹⁷, and X¹⁸ are independently selected from the groupconsisting of N and C(H);

one or more of X¹⁹, X²⁰, and X²¹ is N, and the remaining one(s) is/areC(H);

one or more of X²², X²³, X²⁴, and X²⁵ is N, and the remaining one(s)is/are C(H);

one or more of X²⁶, X²⁷, and X²⁸ is N, and the remaining one(s) is/areC(H);

one or more of X²⁹, X³⁰, X³¹, and X³² is N, and the remaining one(s)is/are C(H);

one or more of X³³, X³⁴, and X³⁵ is N, and the remaining one(s) is/areC(H);

one or more of X³⁶, X³⁷, X³⁸, and X³⁹ is N, and the remaining one(s)is/are C(H);

X⁴⁰, X⁴¹, and X⁴² are independently selected from the group consistingof N and C(H);

one of X⁴³, X⁴⁴, and X⁴⁵ is selected from the group consisting of N(H),O, and S, and the remaining two are C(H)₂;

one of X⁴⁶ and X⁴⁷ is selected from the group consisting of N(H), O, andS, and the other one is C(H)₂;

X⁴⁸, X⁴⁹, X⁵⁰, and X⁵¹ are independently selected from the groupconsisting of N and C(H);

X⁵², X⁵³, and X⁵⁴ are independently selected from the group consistingof N and C(H);

X⁵⁵ is selected from the group consisting of N(H), O, and S;

X⁵⁶, X⁵⁷, and X⁵⁸ are independently selected from the group consistingof N and C(H);

X⁵⁹ is selected from the group consisting of N(H), O, and S;

X⁶⁰ is selected from the group consisting of N(H), O, and S;

X⁶¹, X⁶², X⁶³, and X⁶⁴ are independently selected from the groupconsisting of N and C(H);

X⁶⁵ is selected from the group consisting of N(H), O, and S;

X⁶⁶, X⁶⁷, X⁶⁸, and X⁶⁹ are independently selected from the groupconsisting of N and C(H);

one or more of X⁷⁰, X⁷¹, and X⁷² is N, and the remaining one(s) is/areC(H);

one or more of X⁷³, X⁷⁴, X⁷⁵, and X⁷⁶ is N, and the remaining one(s)is/are C(H); and

one of X⁷⁷ and X⁷⁸ is N(H), and the remaining one is C(H)₂.

In some of the above embodiments, the optionally substituted fused2-ring heterocyclyl is selected from the group consisting of

In some of the above embodiments, the optionally substituted fused2-ring heterocyclyl is selected from the group consisting of:

In some of the above embodiments, X¹, X², and X³ are C(H).

In some of the above embodiments, X⁵, X⁶, and X⁷ are C(H).

In some of the above embodiments, X¹⁰, X¹¹, X¹², and X¹³ are C(H).

In some of the above embodiments, X¹⁵, X¹⁶, X¹⁷, and X¹⁸ are C(H).

In some of the above embodiments, one of X¹⁹, X²⁰, and X²¹ is N.

In some of the above embodiments, one of X²², X²³, X²⁴, and X²⁵ is N.

In some of the above embodiments, one of X²⁶, X²⁷, and X²⁸ is N, and oneof X²⁹, X³⁰, X³¹, and X³² is N.

In some of the above embodiments, X⁴⁰, X⁴¹, and X⁴² are C(H).

In some of the above embodiments, X⁴⁸, X⁴⁹, X⁵⁰, and X⁵¹ are C(H).

In some of the above embodiments, X⁵², X⁵³, and X⁵⁴ are C(H).

In some of the above embodiments, X⁵⁶, X⁵⁷, and X⁵⁸ are C(H).

In some of the above embodiments, X⁶¹, X⁶², X⁶³, and X⁶⁴ are C(H).

In some of the above embodiments, X⁶⁶, X⁶⁷, X⁶⁸, and X⁶⁹ are C(H).

In some of the above embodiments, one or more of X⁷⁰, X⁷¹, and X⁷² is N,and the remaining one(s) is/are C(H).

In some of the above embodiments, one or more of X⁷³, X⁷⁴, X⁷⁵, and X⁷⁶is N, and the remaining one(s) is/are C(H).

B9. Substituent R^(E)

Each R^(E) is independently selected from the group consisting of halo,nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydro,wherein the amino optionally is substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkenyl, andalkynyl.

In some embodiment, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, andaldehydro, wherein the amino optionally is substituted with one or twoindependently selected alkyl.

In some embodiment, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino,aldehydro, and alkylamino.

In some embodiment, each R^(E) is independently selected from the groupconsisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino,imino, aldehydro, and alkylamino.

In some embodiment, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino,and azido. In some such embodiments, each R^(E) is halo. In other suchembodiments, each R^(E) is nitro. In yet other such embodiments, eachR^(E) is hydroxy. In yet other such embodiments, each R^(E) is oxo. Inyet other such embodiments, each R^(E) is carboxy. In yet other suchembodiments, each R^(E) is cyano. In yet other such embodiments, eachR^(E) is amino. In further such embodiments, each R^(E) is imino. In yetfurther such embodiments, each R^(E) is and azido.

In some embodiments, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, andimino.

B10. Substituent R^(F)

Each R^(F) is independently selected from the group consisting of alkyl,alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo,        aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,        wherein:        -   the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl,            and heterocyclyl optionally are substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,            alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino,            hydroxy, and alkyloxy,    -   wherein:        -   amino portion of the alkylsulfonylamino optionally is            substituted with a substituent selected from the group            consisting of alkyl, alkenyl, and alkynyl.

In some embodiment, each R^(F) is independently selected from the groupconsisting of alkyl, alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo,        aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,        wherein:        -   the amino, imino, aminosulfonyl, and aminocarbonyl            optionally are substituted with one or two substituents            independently selected from the group consisting of alkyl,            alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl,            alkynylsulfonyl, and alkylsulfonylamino, wherein:            -   amino portion of the alkylsulfonylamino optionally is                substituted with a substituent selected from the group                consisting of alkyl, alkenyl, and alkynyl.

In some of the above embodiments, each R^(F) is independently selectedfrom the group consisting of the alkyl, alkynyl, and alkynyl, whereinsuch substituents are not substituted.

In some embodiments, each R^(F) is independently selected from the groupconsisting of alkyl, alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl,        alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy,        carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, imino, aminosulfonyl, and aminocarbonyl            optionally are substituted with one or two substituents            independently selected from the group consisting of alkyl,            alkylsulfonyl, and alkylsulfonylamino, wherein:            -   amino portion of the alkylsulfonylamino optionally is                substituted with alkyl.

In some embodiments, each R^(F) is an independently selected alkyloptionally substituted with a substituent selected from the groupconsisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo,aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

-   -   the amino, imino, aminosulfonyl, and aminocarbonyl optionally        are substituted with one or two substituents independently        selected from the group consisting of alkyl, alkylsulfonyl, and        alkylsulfonylamino, wherein:        -   amino portion of the alkylsulfonylamino optionally is            substituted with alkyl.

In some embodiments, each R^(F) is an independently selected alkyloptionally substituted with a substituent selected from the groupconsisting of carboxy, halo, amino, imino, and aminosulfonyl, wherein:

-   -   the amino, imino, and aminosulfonyl optionally are substituted        with one or two substituents independently selected from the        group consisting of alkyl, alkylsulfonyl, and        alkylsulfonylamino.

In some embodiments, each R^(F) is an independently selected alkyloptionally substituted with amino, wherein the amino optionally issubstituted with alkylsulfonyl.

In some embodiments, each R^(F) is an independently selected alkylsubstituted with amino, wherein the amino is substituted withalkylsulfonyl. In some such embodiments, each R^(F) ismethylsulfonylaminomethyl.

In some embodiments, each R^(F) is independently selected from the groupconsisting of alkyl, alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one, two,        or three substituents independently selected from the group        consisting of carboxy, hydroxy, halo, amino, imino, nitro,        azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.

In some embodiments, each R^(F) is independently selected alkylsubstituted with one or more substituents independently selected fromthe group consisting of carboxy, hydroxy, halo, amino, imino, nitro,azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.

B11. Substituent R^(G)

Each R^(G) is independently selected from the group consisting ofcarbocyclyl and heterocyclyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro,        azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,        alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,        alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy,        carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl.

In some of the above embodiments, each R^(G) is independently selectedfrom the group consisting of carbocyclyl and heterocyclyl, wherein suchsubstituents are not substituted.

In some embodiments, each R^(G) is independently selected from the groupconsisting of carbocyclyl and heterocyclyl, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl and            alkylsulfonyl.

In some of the above embodiments, the carbocyclyl is C₃-C₆-carbocyclyl.

In some of the above embodiments, the heterocyclyl is 5-6-memberedheterocyclyl.

B12. Substituent R^(H)

Each R^(H) is independently selected from the group consisting ofalkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy,and alkynylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl.

In some of the above embodiments, each R^(H) is independently selectedfrom the group consisting of alkyloxy, alkenyloxy, alkynyloxy,alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, whereinsuch substituents are not substituted.

In some embodiments, each R^(H) is independently selected from the groupconsisting of alkyloxy and alkylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl and            alkylsulfonyl.

In some embodiments, each R^(H) is independently selected from the groupconsisting of alkyloxy and alkylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and        aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl and            alkylsulfonyl.

In some embodiments, each R^(H) is independently selected from the groupconsisting of alkyloxy and alkylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and        aminocarbonyl.

In some embodiments, each R^(H) is independently selected alkyloxy.

In some embodiments, each R^(H) is independently selectedalkylsulfonyloxy.

B13. Substituent R^(I)

Each R^(I) is independently selected from the group consisting ofalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl,alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl,wherein:

-   -   (a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl,        heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:        -   the carbocyclyl and heterocyclyl optionally are substituted            with one or two substituents independently selected from the            group consisting of halo, alkyl, and oxo.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, andheterocyclylcarbonyl, wherein such substituents are not substituted.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl, aminocarbonyl, alkyloxycarbonyl,carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:

-   -   (a) the alkylcarbonyl optionally is substituted with a        substituent selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, and aminocarbonyl,        and    -   (b) the aminocarbonyl optionally is substituted with a        substituent selected from the group consisting of alkyl,        alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   the aminocarbonyl optionally is substituted with a substituent        selected from the group consisting of alkyl, alkyloxyalkyl,        alkylsulfonyl, and alkylsulfonylamino.

In some embodiment, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, andaminocarbonyl, wherein:

-   -   (a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, and alkylsulfonylamino.

In some of the above embodiments, each R^(I) is independently selectedfrom the group consisting of alkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, and aminocarbonyl, wherein such substituents are notsubstituted.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   (a) the alkylcarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl and alkylsulfonylamino.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   (a) the alkylcarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and        aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl and alkylsulfonylamino.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   the alkylcarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl.

In some embodiments, each R^(I) is independently selected alkylcarbonyl.

In some embodiments, each R^(I) is independently selected aminocarbonyl.

B14. Substituent R^(J)

Each R^(J) is independently selected from the group consisting ofcarbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino,alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino,alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino,alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,alkyloxycarbonylaminoimino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,        alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or more substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy,            halo, nitro, cyano, azido, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or more substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,            and alkynyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy,        alkynyloxy, halo, nitro, cyano, azido, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, and alkynyl.

In some embodiment, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino,alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino,alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino,aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino,and alkynylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,        alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or more substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy,            halo, nitro, cyano, azido, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or more substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,            and alkynyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy,        alkynyloxy, halo, nitro, cyano, azido, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, and alkynyl; and

In some of the above embodiments, each R^(J) is independently selectedfrom the group consisting of carbocyclylsulfonylamino,heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino,alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino,alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein suchsubstituents are not substituted.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylcarbonylamino, alkyloxycarbonylamino, alkylsulfonylamino,aminocarbonylamino, and alkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of such substituents optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or two        substituents independently selected from the group consisting of        alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and        amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected alkyl.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of such substituents optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or two        substituents independently selected from the group consisting of        alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and        amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected alkyl.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   the amino portion of such substituents optionally is substituted        with a substituent independently selected from the group        consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   the alkyl portion of the alkylsulfonylamino and        alkylsulfonylaminoimino optionally is substituted with one or        two substituents independently selected from the group        consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl,        alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,        and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   the carbocyclyl and heterocyclyl portions of such substituents        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl,        carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino and heterocyclylsulfonylamino,wherein:

-   -   the carbocyclyl and heterocyclyl portions of such substituents        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl,        carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.

In some embodiments, each R^(J) is independently selected from the groupconsisting of alkylsulfonylamino, alkenylsulfonylamino,alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or two substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   (a) the amino portion of the alkylsulfonylamino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of the alkylsulfonylamino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the amino portion of the alkylsulfonylamino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the amino portion of the alkylsulfonylamino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the alkyl portion of the alkylsulfonylamino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the alkyl portion of the alkylsulfonylamino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino. In some such embodiments, each R^(J) ismethylsulfonylamino.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of the alkylsulfonylaminoimino optionally        is substituted with a substituent independently selected from        the group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of the alkylsulfonylaminoimino optionally        is substituted with one or two substituents independently        selected from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the amino portion of the alkylsulfonylaminoimino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the amino portion of the alkylsulfonylaminoimino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the alkyl portion of the alkylsulfonylaminoimino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the alkyl portion of the alkylsulfonylaminoimino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino. In some such embodiments, each R^(J) ismethylsulfonylaminoimino.

In some embodiments, each R^(J) is independently selected from the groupconsisting of alkylcarbonylamino and alkyloxycarbonylamino, wherein:

-   -   the alkyl portion of such substituents optionally is substituted        with one or two substituents independently selected from the        group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl,        alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,        and cyano.

B15. Substituent R^(K)

Each R^(K) is independently selected from the group consisting ofaminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl,wherein:

-   -   (a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl; and    -   (b) the aminosulfonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, and alkynyl.

In some of the above embodiments, each R^(K) is independently selectedfrom the group consisting of aminosulfonyl, alkylsulfonyl,alkenylsulfonyl, and alkynylsulfonyl, wherein such substituents are notsubstituted.

In some embodiments, each R^(K) is independently selected from the groupconsisting of aminosulfonyl and alkylsulfonyl, wherein:

-   -   (a) the alkylsulfonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl; and    -   (b) the aminosulfonyl optionally is substituted with one or two        substituents independently selected alkyl.

In some embodiments, each R^(K) is independently selected from the groupconsisting of aminosulfonyl and alkylsulfonyl.

C. Embodiments of Compounds of Formula I

Various embodiments of substituents R¹, R², R³, R⁴, R⁵, L, R^(A), R^(B),R^(C), R^(D), R⁶, R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K)have been discussed above. These substituent embodiments can be combinedto form various embodiments of compounds of formula I. All embodimentsof compounds of formula I formed by combining the substituentembodiments discussed above are within the scope of Applicants'invention, and some illustrative embodiments of the compounds of formulaI are provided below.

In some embodiments, in the compounds of formula I:

is selected from the group consisting of single carbon-carbon bond anddouble carbon-carbon bond;

R¹ is selected from the group consisting of hydrogen and methyl;

R² is selected from the group consisting of hydrogen and halo;

R³ is selected from the group consisting of hydrogen and halo;

R⁴ is selected from the group consisting of C₁-C₄-alkyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with up to three        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and    -   (b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl, halo,        and alkylsulfonylamino;

R⁵ is selected from the group consisting of hydrogen, hydroxy, alkyloxy,and halo;

L is selected from the group consisting of C(R^(A))═C(R^(B)), ethylene,and cyclopropyl-1,2-ene;

one of R^(A) and R^(B) is hydrogen, and the other is selected from thegroup consisting of hydrogen, methyl, methoxy, and halo;

R⁶ is selected from the group consisting of C₅-C₆-carbocyclyl and5-6-membered heterocyclyl, wherein each such substituent is substitutedwith one, two, or three substituents independently selected from thegroup consisting of R^(E), R^(F), and R^(J);

each R^(E) is independently selected from the group consisting ofchloro, fluoro, nitro, hydroxy, oxo, carboxy, amino, imino, aldehydro,and alkylamino;

each R^(F) is an independently selected alkyl optionally substitutedwith a substituent selected from the group consisting of carboxy, halo,amino, imino, and aminosulfonyl, wherein:

-   -   the amino, imino, and aminosulfonyl optionally are substituted        with one or two substituents independently selected from the        group consisting of alkyl, alkylsulfonyl, and        alkylsulfonylamino;

each R^(I) is independently selected from the group consisting ofalkylcarbonyl and aminocarbonyl, wherein:

-   -   the aminocarbonyl optionally is substituted with a substituent        selected from the group consisting of alkyl, alkyloxyalkyl,        alkylsulfonyl, and alkylsulfonylamino; and

each R^(J) is independently selected from the group consisting ofalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, andalkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or two substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein the alkyl            optionally is substituted with one or more hydroxy.

Examples of compounds of formula I (and salts thereof) are shown inTables 1-7 below. The synthesis examples below provide step-by-steppreparation instructions for some of these compounds. The remainingcompounds were prepared utilizing the general method-of-preparationdiscussion, specific synthesis examples below, and/or the discussionthroughout this application.

TABLE 1

compound R⁵ R^(B) substituent(s) IA-L1-1.3 —OCH₃ —Cl -4-N(H)S(O)₂CH₃ [Z]IA-L1-1.4 —OCH₃ —F -4-N(H)S(O)₂CH₃ [Z] IA-L1-1.5 —OCH₃ —F-4-N(H)S(O)₂CH₃ [E] IA-L1-1.6 —OCH₃ —CH₃ -4-N(H)S(O)₂CH₃ [E] IA-L1-1.9—OCH₃ —H -4-N(H)S(O)₂CH₃ [E] IA-L1-1.10 —OCH₃ —H -4-N(H)S(O)₂CH₃ [Z]IA-L1-1.11 —OCH₃ —H -4-N[C(O)CH₃]S(O)₂CH₃ [E] IA-L1-1.12 —OCH₃ —H -4-F[E] IA-L1-1.13 —OCH₃ —H -4-NH₂ [E] IA-L1-1.14 —OCH₃ —H -4-OCH₃ [E]IA-L1-1.16 —H —H -4-N(H)S(O)₂CH₃ [E] IA-L1-1.17 —OCH₃ —OCH₃-4-N(H)S(O)₂CH₃ [Z] IA-L1-1.18 —OCH₃ —H — [E] IA-L1-1.20 —OCH₃ —H-4-N(H)S(O)₂CH₃ [Z] IA-L1-1.21 —OCH₃ —F -4-N(H)S(O)₂CH₃ [Z]:[E] (1:1)IA-L1-1.22 —OCH₃ —H -4-NO₂ [B] IA-L1-1.23 —OCH₃ —Cl -4-NO₂ [Z]IA-L1-1.24 —OCH₃ —CH₃ -4-NO₂ [E] IA-L1-1.25 —H —H -4-NO₂ [E] IA-L1-1.26—OCH₃ —H -3-F and -4-N(H)S(O)₂CH₃ [E] IA-L1-1.27 —OCH₃ —H -2-OCH₃ and-4-N(H)S(O)₂CH₃ [E]

TABLE 2

compound substituent(s) IB-L1-1.1 -4-N(H)S(O)₂CH₃ [E] IB-L1-1.4-2-C(O)OH and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.5 -3-F and -4-N(H)S(O)₂CH₃ [E]IB-L1-1.6 -2-C(O)H and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.7 -2-C(O)OCH₃ and-4-N(H)S(O)₂CH₃ [E] IB-L1-1.8 -2-C(H)═N(OH) and -4-N(H)S(O)₂CH₃ [E]IB-L1-1.9 -2-C(O)N(H)CH₂CH₂OCH₃ and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.10-2-CH₂OH and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.11 -2-C(O)OC(H)₂CH₃ and-4-N(H)S(O)₂CH₃ [E] IB-L1-1.13 -2-C(H)₂OCH₃ and -4-N(H)S(O)₂CH₃ [E]IB-L1-1.14 -2-C(O)N(CH₃)₂ and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.15 -2-CH₃ and-4-N(H)S(O)₂CH₃ and -5-F [E] IB-L1-1.16 imidazol-2-yl and-4-N(H)S(O)₂CH₃ [E] IB-L1-1.17 -2-C(O)N(H)CH₃ and -4-N(H)S(O)₂CH₃ [E]IB-L1-1.18

IB-L1-1.19 -2-C(H)═NOCH₃ and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.21 -2-C(O)NH₂and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.22

IB-L1-1.23

IB-L1-1.24 -2-C(O)N(CH₃)C(H)₂C(H)₂OCH₃ and -4-N(H)S(O)₂CH₃ [E]IB-L1-1.25 -2-C(H)₂OC(H)(CH₃)₂ and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.26

IB-L1-1.27

IB-L1-1.28 -2-NH₂ and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.29

IB-L1-1.31 -2-C(H)₂N(H)C(H)₂C(H)₂C(H)(CH₃)₂ and -4-N(H)S(O)₂CH₃ [E]IB-Li-1.32 -2-N(H)C(O)OC(CH₃)₃ and -4-N(H)S(O)₂CH₃ [E] IB-L1-1.33

IB-L1-1.34 -4-N(H)S(O)₂CH₃ [Z]

TABLE 3

compound R⁴ IB-L1-1.45 —C(CH₃)₂C(H)₂OH [E] IB-L1-1.46 furan-2-yl [E]IB-L1-1.47

IB-L1-1.48

IB-L1-1.49 —S(O)₂CH₃ [E] IB-L1-1.50 furan-3-yl [E] IB-L1-1.51 —I [E]IB-L1-1.52 —Br [E] IB-L1-1.53 pyridin-3-yl [E] IB-L1-1.55 pyridin-4-yl[E]

TABLE 4

compound R² R⁵ IB-L1-1.2 —F —OCH₃ [E] IB-L1-1.12 —H —Cl [E] IB-L1-1.20—Cl —OCH₃ [E] IB-L1-1.30 —H —OCH₂CH₃ [E]

TABLE 5

compound R⁵ IA-L5-2-1.1 —OCH₃ IA-L5-2-1.2 —H

TABLE 6

compound substituent(s) IB-L5-2-1.1 -2-C(O)OCH₃ and -4-N(H)S(O)₂CH₃IB-L5-2-1.2 -4-N(H)S(O)₂CH₃

TABLE 7

IA-L8-1.1

D. Isomers

This invention also is directed, in part, to all isomers of thecompounds of formula I (and their salts) (i.e., structural andstereoisomers). Structural isomers include chain and position isomers.Stereoisomers include E/Z isomers (i.e., isomers with regard to one ormore double bonds), enantiomers (i.e., stereo-isomers that have oppositeconfigurations at all stereogenic centers), and diastereoisomers (i.e.,stereo-isomers that have the same configuration at one or morestereogenic centers, but differ at other stereogenic centers).

E. Salts

This invention also is directed, in part, to all salts of the compoundsof formula I. A salt of a compound may be advantageous due to one ormore of the salt's properties, such as, for example, enhancedpharmaceutical stability in differing temperatures and humidities, or adesirable solubility in water or other solvents. Where a salt isintended to be administered to a patient (as opposed to, for example,being in use in an in vitro context), the salt preferably ispharmaceutically acceptable and/or physiologically compatible. The term“pharmaceutically acceptable” is used adjectivally in this patentapplication to mean that the modified noun is appropriate for use as apharmaceutical product or as a part of a pharmaceutical product.Pharmaceutically acceptable salts include salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. In general, these salts typically may be prepared by conventionalmeans by reacting, for example, the appropriate acid or base with acompound of the invention.

Pharmaceutically acceptable acid addition salts of the compounds offormula I can be prepared from an inorganic or organic acid. Examples ofoften suitable inorganic acids include hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitableorganic acids generally include, for example, aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids. Specific examples of often suitable organic acids includeacetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),ethanesulfonate, benzenesulfonate, pantothenate,2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenicacid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate,alginate, bisulfate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecylsulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmoate,pectinate, 2-naphthalesulfonate, 3-phenylpropionate, picrate, pivalate,thiocyanate, tosylate, and undecanoate.

Pharmaceutically acceptable base addition salts of the compounds offormula I include, for example, metallic salts and organic salts.Preferred metallic salts include alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts, and other physiologically acceptablemetal salts. Such salts may be made from aluminum, calcium, lithium,magnesium, potassium, sodium, and zinc. Preferred organic salts can bemade from amines, such as tromethamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine. Basicnitrogen-containing groups can be quaternized with agents such as loweralkyl (C₁-C₆) halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides), arylalkylhalides (e.g., benzyl and phenethyl bromides), and others.

In some embodiments, the salt is sodium salt of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

In some embodiments, the salt is disodium salt of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

In some embodiments, the salt is potassium salt of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

In some embodiments, the salt is monopotassium salt of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

F. Purity

Compounds of formula I (and salts thereof) with any level of purity(including pure and substantially pure) are within the scope ofApplicants' invention. The term “substantially pure” in reference to acompound/salt/isomer, means that the preparation/composition containingthe compound/salt/isomer contains more than about 85% by weight of thecompound/salt/isomer, preferably more than about 90% by weight of thecompound/salt/isomer, preferably more than about 95% by weight of thecompound/salt/isomer, preferably more than about 97% by weight of thecompound/salt/isomer, and preferably more than about 99% by weight ofthe compound/salt/isomer.

G. Crystalline Forms of Some Specific Compounds and Salts of theInvention G1. Crystalline Forms of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideDisodium Salt

This invention also relates, in part, to crystalline forms of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedisodium salt, namely the nonahydrate and tetrahydrate crystalline formsdiscussed below.

This invention relates, in part, to a nonahydrate crystalline disodiumsalt. The crystallographic unit cell parameters of the nonahydratecrystalline disodium salt have been determined to be as follows: a is8.9 Å, b is 9.4 Å, and c is 20.7 Å (more precisely, a is 8.926(2) Å, bis 9.415(2) Å, and c is 20.674(5)Å); the cell angles are: α—94.8°,β—93.3°, and γ—107.0° (more precisely, α is 94.796(4)°, β is 93.345(4)°,and γ is 107.013(4)°); and the cell volume is 1649 Å³ (more precisely,1649.3(7) Å³). The salt crystallizes in the P-1 space group.

In some embodiments, the disodium salt nonahydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2, 14.7±0.2,16.4±0.2, 17.8±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.9±0.2, and 23.5±0.2degrees 2θ. In some such embodiments, the disodium salt nonahydrate hasan X-ray powder diffraction pattern comprising three or more peaksselected from the group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2,11.6±0.2, 12.9±0.2, 14.7±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.8±0.2,20.8±0.2, 21.9±0.2, and 23.5±0.2 degrees 2θ. In other such embodiments,the disodium salt nonahydrate has an X-ray powder diffraction patterncomprising five or more peaks selected from the group consisting of4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2, 14.7±0.2, 16.4±0.2,17.8±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.9±0.2, and 23.5±0.2 degrees2θ.

In some embodiments, the disodium salt nonahydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2, 14.7±0.2,14.9±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2, 20.8±0.2,20.9±0.2, 21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2θ. In some suchembodiments, the disodium salt nonahydrate has an X-ray powderdiffraction pattern comprising three or more peaks selected from thegroup consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2,14.7±0.2, 14.9±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2,20.8±0.2, 20.9±0.2, 21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2θ. Inother such embodiments, the disodium salt nonahydrate has an X-raypowder diffraction pattern comprising five or more peaks selected fromthe group consisting of 4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2,14.7±0.2, 14.9±0.2, 16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2,20.8±0.2, 20.9±0.2, 21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2θ.

In some embodiments, the disodium salt nonahydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 1. The 2θ values forthe peaks in FIG. 1 (and their intensities) are as follows: 4.31 (100),10.36 (12), 10.91 (23), 11.61 (52), 12.93 (24), 14.73 (65), 14.89 (20),16.44 (41), 17.80 (38), 19.44 (26), 19.67 (37), 19.83 (59), 20.75 (69),20.89 (21), 21.92 (43), 22.13 (40), and 22.42 (24).

This invention also relates, in part, to a process for preparing thedisodium salt nonahydrate. It was prepared in aqueous medium. AqueousNaOH (1M, 1.18 ml) was added to(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide(compound IB-L1-1.1) (27.82 mg) (molar ratio 1:20 acid:base). Theresulting suspension was equilibrated at ambient conditions. Thedisodium salt nonahydrate formed seven days later through asolution-mediated process. Alternatively, the disodium salt nonahydratewas prepared by suspending 278.8 mg of compound IB-L1-1.1 in 1.25 ml THFwhile heated to about 50° C. Aqueous NaOH (1N, 1.5 ml, 2.2 molarequivalents) was added. The solid dissolved completely to yield a clearsolution, which was naturally cooled to ambient temperatures. The saltcrystallized spontaneously. The molecular structure was determined bysingle crystal diffractometry.

This invention relates, in part, to a tetrahydrate crystalline disodiumsalt.

In some embodiments, the disodium salt tetrahydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2,21.6±0.2, 25.0±0.2, and 29.5±0.2 degrees 2θ. In some such embodiments,the disodium salt tetrahydrate has an X-ray powder diffraction patterncomprising three or more peaks selected from the group consisting of4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2,25.0±0.2, and 29.5±0.2 degrees 2θ. In other such embodiments, thedisodium salt tetrahydrate has an X-ray powder diffraction patterncomprising five or more peaks selected from the group consisting of4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2,25.0±0.2, and 29.5±0.2 degrees 2θ.

In some embodiments, the disodium salt tetrahydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2, 17.0±0.2, 17.5±0.2,20.9±0.2, 21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2 degrees 2θ. In somesuch embodiments, the disodium salt tetrahydrate has an X-ray powderdiffraction pattern comprising three or more peaks selected from thegroup consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2, 17.0±0.2,17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2 degrees2θ. In other such embodiments, the disodium salt tetrahydrate has anX-ray powder diffraction pattern comprising five or more peaks selectedfrom the group consisting of 4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2,17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2degrees 2θ.

In some embodiments, the disodium salt tetrahydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 2. The 2θ values forthe peaks in FIG. 2 (and their intensities) are as follows: 4.81 (100),12.07 (7), 14.01 (27), 14.41 (8), 16.96 (18), 17.53 (11), 20.87 (18),21.58 (22), 24.99 (11), 29.47 (9), and 34.20 (9).

This invention also relates, in part, to a process for preparing thedisodium salt tetrahydrate by suspending the nonahydrate disodium saltin an organic solvent (e.g., ethanol, 1-propanol, or 2-propanol).

G2. Crystalline Form of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideDipotassium Salt

This invention also relates, in part, to a crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedipotassium salt tetrahydrate.

The crystallographic unit cell parameters of the dipotassium salttetrahydrate have been determined to be as follows: a is 14.5 Å, b is10.8 Å, and c is 35.8 Å (more precisely, a is 14.454(14) Å, b is10.763(14) Å, and c is 35.75(4) Å); the cell angle is: β—98.8° (moreprecisely, β is 98.82(3)°); and the cell volume is 5499 Å³ (moreprecisely, 5499(111) Å³). The salt crystallizes in the C2/c space group.

In some embodiments, the dipotassium salt tetrahydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 13.7±0.2, 15.0±0.2,16.5±0.2, 17.1±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 24.0±0.2, 26.4±0.2,and 29.3±0.2 degrees 2θ. In some such embodiments, the dipotassium salttetrahydrate has an X-ray powder diffraction pattern comprising three ormore peaks selected from the group consisting of 5.0±0.2, 11.9±0.2,12.4±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 17.1±0.2, 20.8±0.2, 21.3±0.2,22.2±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2θ. In other suchembodiments, the dipotassium salt tetrahydrate has an X-ray powderdiffraction pattern comprising five or more peaks selected from thegroup consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 13.7±0.2, 15.0±0.2,16.5±0.2, 17.1±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 24.0±0.2, 26.4±0.2,and 29.3±0.2 degrees 2θ.

In some embodiments, the dipotassium salt tetrahydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2,15.0±0.2, 16.5±0.2, 16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2,22.2±0.2, 22.4±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2θ. In somesuch embodiments, the dipotassium salt tetrahydrate has an X-ray powderdiffraction pattern comprising three or more peaks selected from thegroup consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2,15.0±0.2, 16.5±0.2, 16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2,22.2±0.2, 22.4±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2θ. Inother such embodiments, the dipotassium salt tetrahydrate has an X-raypowder diffraction pattern comprising five or more peaks selected fromthe group consisting of 5.0±0.2, 11.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2,15.0±0.2, 16.5±0.2, 16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2,22.2±0.2, 22.4±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2θ.

In some embodiments, the dipotassium salt tetrahydrate has an X-raypowder diffraction pattern substantially as shown in FIG. 4. The 2θvalues for the peaks in FIG. 4 (and their intensities) are as follows:5.00 (100), 11.86 (34), 12.39 (32), 12.64 (19), 13.70 (23), 15.03 (21),16.47 (24), 16.66 (24), 17.12 (28), 20.75 (29), 20.81 (33), 21.34 (22),22.15 (46), 22.38 (31), 24.02 (24), 26.44 (24), and 29.32 (21).

This invention also relates, in part, to a process for preparing thedipotassium salt tetrahydrate by suspending compound IB-L1-1.1 (261.13mg) in 1.25 ml THF while heated to about 50° C. Aqueous KOH (1N, 1.3 ml,2.2 molar equivalent) was added. The solid dissolved completely to yielda clear solution, which was naturally cooled to ambient temperatures.Crystallization occurred during the slow evaporation process.

G3. Crystalline Forms of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideMonopotassium Salt

This invention also relates, in part, to crystalline forms of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt, namely the trihydrate and dihydrate crystallineforms discussed below.

This invention relates, in part, to a monopotassium salt trihydrate. Thecrystallographic unit cell parameters of the trihydrate crystallinemonopotassium salt have been determined to be as follows: a is 9.0 Å, bis 8.3 Å, and c is 18.6 Å (more precisely, a is 9.0393(16) Å, b is8.3332(15) Å, and c is 18.582(3) Å); the cell angles are: α—80.5°,β—85.1°, and γ—80.5° (more precisely, α is 80.511(2)°, β is 85.134(3)°,and γ is 80.531(2)°); and the cell volume is 1359 Å³ (more precisely,1359.3(4) Å³). The salt crystallizes in the P-1 space group.

In some embodiments, the monopotassium salt trihydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2,16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees2θ. In some such embodiments, the monopotassium salt trihydrate has anX-ray powder diffraction pattern comprising three or more peaks selectedfrom the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2,15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2degrees 2θ. In other such embodiments, the monopotassium salt trihydratehas an X-ray powder diffraction pattern comprising five or more peaksselected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2,13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2,and 23.0±0.2 degrees 2θ.

In some embodiments, the monopotassium salt trihydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2,15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2,22.6±0.2, and 23.0±0.2 degrees 2θ. In some such embodiments, themonopotassium salt trihydrate has an X-ray powder diffraction patterncomprising three or more peaks selected from the group consisting of4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2,21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2degrees 2θ. In other such embodiments, the monopotassium salt trihydratehas an X-ray powder diffraction pattern comprising five or more peaksselected from the group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2,13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2,22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2 degrees 2θ.

In some embodiments, the monopotassium salt trihydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2,15.3±0.2, 16.9±0.2, 21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2,22.6±0.2, and 23.0±0.2 degrees 2θ. In some such embodiments, themonopotassium salt trihydrate has an X-ray powder diffraction patterncomprising three or more peaks selected from the group consisting of4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2,21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 2θ. In other suchembodiments, the monopotassium salt trihydrate has an X-ray powderdiffraction pattern comprising five or more peaks selected from thegroup consisting of 4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2,16.9±0.2, 21.2±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees2θ.

In some embodiments, the monopotassium salt trihydrate has an X-raypowder diffraction pattern substantially as shown in FIG. 5. The 2θvalues for the peaks in FIG. 5 (and their intensities) are as follows:4.83 (60), 10.79 (100), 11.31 (22), 13.42 (41), 13.59 (18), 15.32 (21),16.90 (38), 21.24 (22), 21.68 (20), 21.68 (21), 22.15 (22), 22.55 (29),22.63 (23), and 23.02 (27).

This invention also relates, in part, to a process for preparing themonopotassium salt trihydrate. It was prepared by suspending compoundIB-L1-1.1 (108.81 mg) in 0.4 ml THF while heated to about 50° C. AqueousKOH solution (1N, 0.278 ml, 1.2 molar equivalent) was added. The soliddissolved completely to yield a clear solution. Additional 1.6 ml THFwas added to the solution, which was then naturally cooled to ambienttemperatures and crystallization was observed. Alternatively, themonopotassium salt trihydrate was prepared by suspending compoundIB-L1-1.1 (343.89 mg) in 1.0 ml THF while heated to 50° C. Aqueous KOH(1 N, 0.878 ml, 1.2 molar equivalent) was added. The solid dissolvedcompletely to yield a clear solution. Ethanol was added to the solutiondropwise to a total volume of 4.0 ml. The solution was then naturallycooled to ambient temperature and crystallization was observed.

This invention relates, in part, to a monopotassium salt dihydrate.

In some embodiments, the monopotassium salt dihydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 7.7±0.2, 8.8±0.2, 16.1±0.2, and 19.7±0.2 degrees2θ. In some such embodiments, the monopotassium salt dihydrate has anX-ray powder diffraction pattern comprising three or more peaks selectedfrom the group consisting of degrees 2θ.

In some embodiments, the monopotassium salt dihydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1±0.2,17.7±0.2, 19.2±0.2, 19.7±0.2, 23.1±0.2, and 29.2±0.2 degrees 2θ. In somesuch embodiments, the monopotassium salt dihydrate has an X-ray powderdiffraction pattern comprising three or more peaks selected from thegroup consisting of 7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1±0.2,17.7±0.2, 19.2±0.2, 19.7±0.2, 23.1±0.2, and 29.2±0.2 degrees 2θ. Inother such embodiments, the monopotassium salt dihydrate has an X-raypowder diffraction pattern comprising five or more peaks selected fromthe group consisting of 7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1±0.2,17.7±0.2, 19.2±0.2, 19.7±0.2, 23.1±0.2, and 29.2±0.2 degrees 2θ.

In some embodiments, the monopotassium salt dihydrate has an X-raypowder diffraction pattern substantially as shown in FIG. 6. The 2θvalues for the peaks in FIG. 6 (and their intensities) are as follows:7.68 (19), 8.83 (100), 12.40 (7), 13.97 (10), 16.12 (25), 17.75 (9),19.22 (12), 19.73 (40), 23.05 (9), and 29.21 (7).

This invention also relates, in part, to a process for preparing themonopotassium salt dihydrate. It was prepared by suspending themonopotassium salt trihydrate in media of low water activity, such as anethanol/H₂O mixture (50/1 v/v). Alternatively, the monopotassium saltdihydrate was prepared by dissolving potassium trihydrate solid (1.8 g)in 36 mL of IPA and 4 ml water at 80° C. The resulting solution wascooled to 55° C. over 1 h. The solution was then seeded with 7.5 mg ofdihydrate crystals at 55° C. and maintained at 55° C. for 1 h. Heptane(36 ml) was then added over 3 h. The reaction mixture was cooled to 0°C., and filtration yielded a material containing both di- and trihydratecrystals. The solid was then reslurried in 20 mL of 10:1 v/v EtOH/H₂O at50° C. for 3 h and cooled to 25° C. over 5 h. The slurry was then mixedat 25° C. for additional 3 days and cooled to 0° C. over 3 h and held atthis temperature for 2 h. The resulting crystals were filtered andair-dried on filter funnel for 1 h to give dihydrate. The dihydratemonopotassium salt was also prepared by slurrying a mixture of dihydrateand trihydrate crystals in 10:1 v/v EtOH/H₂O at 80° C. for 2 days. Thepotassium content was confirmed by ion chromatography.

G4. Crystalline Form of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide1/7 Potassium Salt

This invention also relates, in part, to a crystalline form of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide1/7 potassium salt.

In some embodiments, the 1/7 potassium salt has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2,13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2,19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 21.2±0.2, 22.1±0.2, and 22.9±0.2degrees 2θ. In some such embodiments, the 1/7 potassium salt has anX-ray powder diffraction pattern comprising three or more peaks selectedfrom the group consisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2,11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2,18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 21.2±0.2,22.1±0.2, and 22.9±0.2 degrees 2θ. In other such embodiments, the 1/7potassium salt has an X-ray powder diffraction pattern comprising fiveor more peaks selected from the group consisting of 7.7±0.2, 8.3±0.2,10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2, 16.3±0.2,16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2, 20.2±0.2,20.5±0.2, 21.2±0.2, 22.1±0.2, and 22.9±0.2 degrees 2θ.

In some embodiments, the 1/7 potassium salt has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2,13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2,19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2,22.9±0.2, 24.3±0.2, 24.9±0.2, and 25.1±0.2 degrees 2θ. In some suchembodiments, the 1/7 potassium salt has an X-ray powder diffractionpattern comprising three or more peaks selected from the groupconsisting of 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2,13.4±0.2, 15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2,19.4±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2,22.9±0.2, 24.3±0.2, 24.9±0.2, and 25.1±0.2 degrees 2θ. In other suchembodiments, the 1/7 potassium salt has an X-ray powder diffractionpattern comprising five or more peaks selected from the group consistingof 7.7±0.2, 8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2,15.6±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2,19.9±0.2, 20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2, 22.9±0.2,24.3±0.2, 24.9±0.2, and 25.1±0.2 degrees 2θ.

In some embodiments, the 1/7 potassium salt has an X-ray powderdiffraction pattern substantially as shown in FIG. 8. The 2θ values forthe peaks in FIG. 8 (and their intensities) are as follows: 7.71 (19),8.33 (34), 10.10 (100), 10.66 (29), 11.39 (27), 12.04 (22), 13.39 (39),15.56 (41), 16.27 (62), 16.69 (70), 17.22 (59), 18.31 (18), 18.78 (47),19.44 (36), 19.89 (28), 20.19 (33), 20.54 (87), 20.80 (33), 21.15 (47),22.05 (24), 22.82 (67), 24.32 (22), 24.87 (22), and 25.07 (33).

This invention also relates, in part, to a process for preparing the 1/7potassium salt. It was prepared by suspending compound IB-L1-1.1 (2 g) 6ml THF at 50° C. One molar equivalent of KOH dissolved in 4.3 ml waterwas added, and the reaction mixture was heated to 65° C. to dissolve allsolids. The solution was then cooled to ambient temperatures over 2 hand spontaneous crystallization took place. The slurry was then cooledto 5° C. and held at that temperature for 2 h. The pale yellow crystalswere filtered and air-dried for 24 h at ambient conditions. Thepotassium content was determined by ion chromatography.

G5. Crystalline Form of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideMonodiethylamine Salt Tetrahydrate

This invention also relates, in part, to crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonodiethylamine salt tetrahydrate.

In some embodiments, the monodiethylamine salt tetrahydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2,16.8±0.2, 17.6±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, and 29.8±0.2degrees 2θ. In some such embodiments, the monodiethylamine salttetrahydrate has an X-ray powder diffraction pattern comprising three ormore peaks selected from the group consisting of 9.5±0.2, 10.0±0.2,11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.8±0.2, 20.8±0.2,21.4±0.2, 21.8±0.2, and 29.8±0.2 degrees 2θ. In other such embodiments,the monodiethylamine salt tetrahydrate has an X-ray powder diffractionpattern comprising five or more peaks selected from the group consistingof 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2,19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, and 29.8±0.2 degrees 2θ.

In some embodiments, the monodiethylamine salt tetrahydrate has an X-raypowder diffraction pattern comprising one or more peaks selected fromthe group consisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2,16.8±0.2, 17.6±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2,21.9±0.2, and 29.8±0.2 degrees 2θ. In some such embodiments, themonodiethylamine salt tetrahydrate has an X-ray powder diffractionpattern comprising three or more peaks selected from the groupconsisting of 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2,17.6±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, 21.9±0.2,and 29.8±0.2 degrees 2θ. In other such embodiments, the monodiethylaminesalt tetrahydrate has an X-ray powder diffraction pattern comprisingfive or more peaks selected from the group consisting of 9.5±0.2,10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2, 19.4±0.2,19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, 21.9±0.2, and 29.8±0.2 degrees2θ.

In some embodiments, the monodiethylamine salt tetrahydrate has an X-raypowder diffraction pattern substantially as shown in FIG. 9. The 2θvalues for the peaks in FIG. 9 (and their intensities)

are as follows: 9.45 (100), 9.97 (31), 11.85 (67), 12.09 (16), 14.38(22), 16.80 (9), 17.59 (10), 19.39 (8), 19.83 (21), 20.85 (25), 21.37(12), 21.75 (34), 21.87 (8), and 29.78 (7).

This invention also relates, in part, to a process for preparing themonodiethylamine salt tetrahydrate. It was prepared in aqueous medium.Compound IB-L1-1.1 was slowly added to 500 ul of 1M diethylamine untilno more solid can be dissolved into the solution. The solution was thenevaporated slowly at ambient temperatures and the salt crystallized 2days later. Alternatively, the monodiethylamine salt tetrahydrate wasprepared by suspending 64.15 mg of compound IB-L1-1.1 in 400 ul 1Mdiethylamine while heated to 50° C. About 5 drops of THF (˜20 ul) wasadded. The solid dissolved completely upon addition to yield a clearsolution. The solution was then evaporated at ambient temperature, andthe salt crystallized 4 days later. The stoichiometry of the salt wasconfirmed by solution ¹H NMR.

G6. Crystalline Forms of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.1

This invention also relates, in part, to crystalline forms of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide(compound IB-L1-1.1), namely the true polymorphs (pattern A, pattern B,pattern C, and pattern D) and hydrate (pattern AH, pattern BH, patternCH, and pattern DH) crystalline forms discussed below.

G6A. IB-L1-1.1 True Polymorphs

This invention relates, in part, to pattern A crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

In some embodiments, the pattern A polymorph has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.5±0.2, 18.8±0.2,22.7±0.2, and 29.2±0.2 degrees 2θ. In some such embodiments, the patternA polymorph has an X-ray powder diffraction pattern comprising three ormore peaks selected from the group consisting of 5.8±0.2, 9.9±0.2,11.8±0.2, 12.4±0.2, 14.5±0.2, 18.8±0.2, 22.7±0.2, and 29.2±0.2 degrees2θ. In other such embodiments, the pattern A polymorph has an X-raypowder diffraction pattern comprising five or more peaks selected fromthe group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.5±0.2,18.8±0.2, 22.7±0.2, and 29.2±0.2 degrees 2θ.

In some embodiments, the pattern A polymorph has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.0±0.2, 14.5±0.2,15.3±0.2, 18.5±0.2, 18.8±0.2, 22.2±0.2, 22.7±0.2, 23.8±0.2, 26.0±0.2,and 29.2±0.2 degrees 2θ. In some such embodiments, the pattern Apolymorph has an X-ray powder diffraction pattern comprising three ormore peaks selected from the group consisting of 5.8±0.2, 9.9±0.2,11.8±0.2, 12.4±0.2, 14.0±0.2, 14.5±0.2, 15.3±0.2, 18.5±0.2, 18.8±0.2,22.2±0.2, 22.7±0.2, 23.8±0.2, 26.0±0.2, and 29.2±0.2 degrees 2θ. Inother such embodiments, the pattern A polymorph has an X-ray powderdiffraction pattern comprising five or more peaks selected from thegroup consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2, 12.4±0.2, 14.0±0.2,14.5±0.2, 15.3±0.2, 18.5±0.2, 18.8±0.2, 22.2±0.2, 22.7±0.2, 23.8±0.2,26.0±0.2, and 29.2±0.2 degrees 2θ.

In some embodiments, the pattern A polymorph has an X-ray powderdiffraction pattern substantially as shown in FIG. 11. The 2θ values forthe peaks in FIG. 11 (and their intensities) are as follows: 5.85 (28),9.88 (51), 11.79 (73), 12.38 (56), 14.03 (38), 14.45 (100), 15.27 (29),18.52 (39), 18.80 (47), 22.24 (40), 22.72 (77), 23.76 (39), 25.98 (22),and 29.21 (64).

This invention also relates, in part, to a process for preparing patternA polymorph. Pattern A polymorph was prepared as discussed in Example Ebelow.

This invention relates, in part, to pattern B crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

In some embodiments, the pattern B polymorph has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 11.5±0.2, 13.3±0.2, 15.4±0.2, 16.4±0.2, 17.1±0.2,18.6±0.2, 19.4±0.2, 20.4±0.2, 21.6±0.2, 22.4±0.2, 24.0±0.2, 26.8±0.2,and 29.0±0.2 degrees 2θ. In some such embodiments, the pattern Bpolymorph has an X-ray powder diffraction pattern comprising three ormore peaks selected from the group consisting of 11.5±0.2, 13.3±0.2,15.4±0.2, 16.4±0.2, 17.1±0.2, 18.6±0.2, 19.4±0.2, 20.4±0.2, 21.6±0.2,22.4±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2θ. In other suchembodiments, the pattern B polymorph has an X-ray powder diffractionpattern comprising five or more peaks selected from the group consistingof 11.5±0.2, 13.3±0.2, 15.4±0.2, 16.4±0.2, 17.1±0.2, 18.6±0.2, 19.4±0.2,20.4±0.2, 21.6±0.2, 22.4±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees2θ.

In some embodiments, the pattern B polymorph has an X-ray powderdiffraction pattern substantially as shown in FIG. 13. The 2θ values forthe peaks in FIG. 13 (and their intensities) are as follows: 11.52 (71),13.30 (87), 15.37 (100), 16.42 (60), 17.13 (69), 18.60 (97), 19.37 (56),20.40 (62), 21.55 (55), 22.41 (39), 23.99 (33), 26.81 (31), and 28.98(50).

This invention relates, in part, to pattern C crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

In some embodiments, the pattern C polymorph has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 7.7±0.2, 10.1±0.2, 10.6±0.2, 12.0±0.2, 13.4±0.2, 16.2±0.2,19.4±0.2, 20.5±0.2, 21.4±0.2, 22.0±0.2, 22.6±0.2, 24.3±0.2, and 27.6±0.2degrees 2θ. In some such embodiments, the pattern C polymorph has anX-ray powder diffraction pattern comprising three or more peaks selectedfrom the group consisting of 7.7±0.2, 10.1±0.2, 10.6±0.2, 12.0±0.2,13.4±0.2, 16.2±0.2, 19.4±0.2, 20.5±0.2, 21.4±0.2, 22.0±0.2, 22.6±0.2,24.3±0.2, and 27.6±0.2 degrees 2θ. In other such embodiments, thepattern C polymorph has an X-ray powder diffraction pattern comprisingfive or more peaks selected from the group consisting of 7.7±0.2,10.1±0.2, 10.6±0.2, 12.0±0.2, 13.4±0.2, 16.2±0.2, 19.4±0.2, 20.5±0.2,21.4±0.2, 22.0±0.2, 22.6±0.2, 24.3±0.2, and 27.6±0.2 degrees 2θ.

In some embodiments, the pattern C polymorph has an X-ray powderdiffraction pattern substantially as shown in FIG. 14. The 2θ values forthe peaks in FIG. 14 (and their intensities) are as follows: 7.69 (27),10.13 (27), 10.64 (49), 12.01 (31), 13.39 (33), 16.25 (91), 19.44 (46),20.49 (100), 21.40 (35), 22.03 (37), 22.60 (30), 24.32 (23), and 27.55(27).

This invention relates, in part, to pattern D crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

In some embodiments, the pattern D polymorph has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2,19.9±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 2θ. In some suchembodiments, the pattern D polymorph has an X-ray powder diffractionpattern comprising three or more peaks selected from the groupconsisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2,19.9±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 2θ. In other suchembodiments, the pattern D polymorph has an X-ray powder diffractionpattern comprising five or more peaks selected from the group consistingof 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2, 19.9±0.2,22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees 2θ.

In some embodiments, the pattern D polymorph has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2, 16.9±0.2,17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2 degrees2θ. In some such embodiments, the pattern D polymorph has an X-raypowder diffraction pattern comprising three or more peaks selected fromthe group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2, 16.1±0.2,16.9±0.2, 17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2degrees 2θ. In other such embodiments, the pattern D polymorph has anX-ray powder diffraction pattern comprising five or more peaks selectedfrom the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2, 15.2±0.2,16.1±0.2, 16.9±0.2, 17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2, 24.7±0.2,and 26.0±0.2 degrees 2θ.

In some embodiments, the pattern D polymorph has an X-ray powderdiffraction pattern substantially as shown in FIG. 15. The 2θ values forthe peaks in FIG. 15 (and their intensities) are as follows: 5.81 (24),10.70 (91), 11.23 (60), 15.17 (28), 16.10 (48), 16.89 (100), 17.10 (42),19.88 (81), 20.12 (100), 22.12 (59), 24.72 (37), and 25.91 (24).

This invention also relates, in part, to a process for preparing patternB, C, and D polymorphs by heating pattern A polymorph to about 160,about 225, and about 268° C., respectively using DSC.

G6B. IB-L1-1.1 Hydrates

This invention also relates, in part, to hydrates of compound IB-L1-1.1,namely to hydrates A, B, C, D, and E discussed below.

This invention relates, in part, to a pattern A(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate.

In some embodiments, the pattern A hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 5.1±0.2, 7.9±0.2, 9.5±0.2, 10.3±0.2, 13.7±0.2, 16.5±0.2,17.1±0.2, 17.5±0.2, 18.8±0.2, 19.2±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2,25.8±0.2, 26.8±0.2, and 28.4±0.2 degrees 2θ. In some such embodiments,the pattern A hydrate has an X-ray powder diffraction pattern comprisingthree or more peaks selected from the group consisting of 5.1±0.2,7.9±0.2, 9.5±0.2, 10.3±0.2, 13.7±0.2, 16.5±0.2, 17.1±0.2, 17.5±0.2,18.8±0.2, 19.2±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2, 25.8±0.2, 26.8±0.2,and 28.4±0.2 degrees 2θ. In other such embodiments, the pattern Ahydrate has an X-ray powder diffraction pattern comprising five or morepeaks selected from the group consisting of 5.1±0.2, 7.9±0.2, 9.5±0.2,10.3±0.2, 13.7±0.2, 16.5±0.2, 17.1±0.2, 17.5±0.2, 18.8±0.2, 19.2±0.2,20.7±0.2, 21.3±0.2, 21.6±0.2, 25.8±0.2, 26.8±0.2, and 28.4±0.2 degrees2θ.

In some embodiments, the pattern A hydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 16. The 2θ values forthe peaks in FIG. 16 (and their intensities) are as follows: 5.13 (13),7.87 (80), 9.45 (100), 10.29 (60), 13.7 (28), 16.54 (30), 17.07 (17),17.51 (40), 18.80 (99), 19.18 (74), 20.69 (21), 21.25 (21), 21.63 (23),25.85 (32), 26.81 (20), and 28.35 (27).

This invention also relates, in part, to a process for preparing thepattern A hydrate by suspending pattern A polymorph (discussed above) inethyl acetate. The recovered pattern A hydrate contains ˜1 watermolecules per molecule of compound IB-L1-1.1.

This invention also relates, in part, to a pattern B(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate.

In some embodiments, the pattern B hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 14.9±0.2,15.4±0.2, 16.4±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2,24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2θ. In some such embodiments,the pattern B hydrate has an X-ray powder diffraction pattern comprisingthree or more peaks selected from the group consisting of 6.3±0.2,7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2,18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2,and 29.0±0.2 degrees 2θ. In other such embodiments, the pattern Bhydrate has an X-ray powder diffraction pattern comprising five or morepeaks selected from the group consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2,12.7±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 18.9±0.2,19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees2θ.

In some embodiments, the pattern B hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2,14.9±0.2, 15.4±0.2, 16.4±0.2, 18.5±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2,22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2θ. In somesuch embodiments, the pattern B hydrate has an X-ray powder diffractionpattern comprising three or more peaks selected from the groupconsisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2,14.9±0.2, 15.4±0.2, 16.4±0.2, 18.5±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2,22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2θ. Inother such embodiments, the pattern B hydrate has an X-ray powderdiffraction pattern comprising five or more peaks selected from thegroup consisting of 6.3±0.2, 7.7±0.2, 10.4±0.2, 12.7±0.2, 13.3±0.2,13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.5±0.2, 18.6±0.2, 18.9±0.2,19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees2θ.

In some embodiments, the pattern B hydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 18. The 2θ values forthe peaks in FIG. 18 (and their intensities) are as follows: 6.31 (7),7.72 (14), 10.45 (24), 12.67 (26), 13.30 (88), 13.50 (44), 14.89 (70),15.40 (100), 16.43 (43), 18.46 (47), 18.63 (86), 18.91 (26), 19.42 (33),22.52 (47), 23.52 (44), 24.02 (20), 26.82 (40), and 28.97 (49).

This invention also relates, in part, to a process for preparing thepattern B hydrate by suspending pattern A polymorph (discussed above) inacetonitrile/water (9/1 v/v). The recovered pattern B hydrate contains˜0.7 water molecules per molecule of compound IB-L1-1.1.

This invention also relates, in part, to a pattern C(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate.

In some embodiments, the pattern C hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 10.5±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2,18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2degrees 2θ. In some such embodiments, the pattern C hydrate has an X-raypowder diffraction pattern comprising three or more peaks selected fromthe group consisting of 10.5±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2,16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2,and 29.0±0.2 degrees 2θ. In other such embodiments, the pattern Chydrate has an X-ray powder diffraction pattern comprising five or morepeaks selected from the group consisting of 10.5±0.2, 13.3±0.2,14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2,23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2θ.

In some embodiments, the pattern C hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 10.5±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2,16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2,and 29.0±0.2 degrees 2θ. In some such embodiments, the pattern C hydratehas an X-ray powder diffraction pattern comprising three or more peaksselected from the group consisting of 10.5±0.2, 13.3±0.2, 13.5±0.2,14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2,23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2θ. In other such embodiments,the pattern C hydrate has an X-ray powder diffraction pattern comprisingfive or more peaks selected from the group consisting of 10.5±0.2,13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2,19.4±0.2, 22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2θ.

In some embodiments, the pattern C hydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 20. The 2θ values forthe peaks in FIG. 20 (and their intensities) are as follows: 10.47 (21),13.31 (56), 13.49 (31), 14.91 (28), 15.40 (86), 16.43 (48), 18.61 (100),18.96 (20), 19.44 (19), 22.55 (26), 23.54 (39), 26.84 (29), and 28.99(54).

This invention also relates, in part, to a process for preparing thepattern C hydrate by suspending pattern A polymorph (discussed above) inwater. The recovered pattern C hydrate contains ˜1 water molecules permolecule of compound IB-L1-1.1.

This invention also relates, in part, to a pattern D(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate.

The crystallographic unit cell parameters of the pattern D hydrate salthave been determined to be as follows: a is 17.8 Å, b is 9.6 Å, and c is27.0 Å (more precisely, a is 17.783(2) Å, b is 9.5651(12) Å, and c is27.014(4) Å); the cell angle is: β—93.3° (more precisely, β is93.256(2)°); and the cell volume is 4588 Å³ (more precisely, 4587.5(10)Å³). The salt crystallizes in the C2/c space group.

In some embodiments, the pattern D hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, 11.1±0.2, 11.6±0.2, 12.2±0.2,14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2,21.4±0.2, 22.7±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 25.2±0.2, 27.2±0.2,29.1±0.2, and 31.0±0.2 degrees 2θ. In some such embodiments, the patternD hydrate has an X-ray powder diffraction pattern comprising three ormore peaks selected from the group consisting of 6.6±0.2, 10.0±0.2,10.5±0.2, 11.1±0.2, 11.6±0.2, 12.2±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2,17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 23.1±0.2,23.6±0.2, 24.6±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees2θ. In other such embodiments, the pattern D hydrate has an X-ray powderdiffraction pattern comprising five or more peaks selected from thegroup consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, 11.1±0.2, 11.6±0.2,12.2±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2,19.3±0.2, 21.4±0.2, 22.7±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 25.2±0.2,27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2θ.

In some embodiments, the pattern D hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, 11.1±0.2, 11.6±0.2, 12.2±0.2,12.5±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2,19.3±0.2, 21.4±0.2, 22.7±0.2, 22.8±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2,24.9±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2θ. In somesuch embodiments, the pattern D hydrate has an X-ray powder diffractionpattern comprising three or more peaks selected from the groupconsisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, 11.1±0.2, 11.6±0.2, 12.2±0.2,12.5±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2,19.3±0.2, 21.4±0.2, 22.7±0.2, 22.8±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2,24.9±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees 2θ. Inother such embodiments, the pattern D hydrate has an X-ray powderdiffraction pattern comprising five or more peaks selected from thegroup consisting of 6.6±0.2, 10.0±0.2, 10.5±0.2, 11.1±0.2, 11.6±0.2,12.2±0.2, 12.5±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2, 17.7±0.2, 18.5±0.2,18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 22.8±0.2, 23.1±0.2, 23.6±0.2,24.6±0.2, 24.9±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees2θ.

In some embodiments, the pattern D hydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 22. The 2θ values forthe peaks in FIG. 22 (and their intensities) are as follows: 6.55 (10),9.96 (12), 10.51 (37), 11.09 (31), 11.62 (100), 12.24 (44), 12.54 (40),14.22 (15), 16.62 (68), 17.07 (22), 17.77 (21), 18.52 (82), 18.84 (47),19.30 (63), 21.45 (34), 22.67 (30), 22.80 (34), 23.08 (20), 23.57 (58),24.63 (73), 24.88 (26), 25.24 (21), 27.23 (36), 29.06 (41), and 31.04(21).

This invention also relates, in part, to a process for preparing thepattern D hydrate. It was prepared by suspending pattern A polymorph(discussed above) in ethanol. Alternatively, it was prepared bysuspending compound IB-L1-1.1 (103.03 mg) in 400 ul THF while heated toabout 55° C. Aqueous NaOH (1M, 264 ul, 1.2 molar equivalent) was added.The solid dissolved completely to yield a clear solution. Ethanol (1.6ml) was added to the solution. The solution was allowed to coolnaturally to ambient temperatures. Crystals were formed during the slowevaporation process. Although it appears that the lattice canaccommodate as much as 0.5 water molecules per molecule of compoundIB-L1-1.1, the recovered pattern D hydrate contained ˜0.2 watermolecules per molecule of compound IB-L1-1.1.

This invention also relates, in part, to a pattern E(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate.

The crystallographic unit cell parameters of the pattern E hydratecrystalline disodium salt have been determined to be as follows: a is9.5 Å, b is 14.5 Å, and c is 17.3 Å (more precisely, a is 9.462(2) Å, bis 14.462(3) Å, and c is 17.281(4) Å); the cell angles are: α—84.9°,β—80.8°, and γ—81.8° (more precisely, a is 84.863(4)°, is 80.760(4)°,and γ is 81.751(4)°); and the cell volume is 2304 Å³ (more precisely,2304.4(9)Å³). The salt crystallizes in the P-1 space group.

In some embodiments, the pattern E hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2,19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2θ. In somesuch embodiments, the pattern E hydrate has an X-ray powder diffractionpattern comprising three or more peaks selected from the groupconsisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2,19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2θ. Inother such embodiments, the pattern E hydrate has an X-ray powderdiffraction pattern comprising five or more peaks selected from thegroup consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.7±0.2, 12.1±0.2,16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees2θ.

In some embodiments, the pattern E hydrate has an X-ray powderdiffraction pattern comprising one or more peaks selected from the groupconsisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.4±0.2, 10.7±0.2, 12.1±0.2,16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees2θ. In some such embodiments, the pattern E hydrate has an X-ray powderdiffraction pattern comprising three or more peaks selected from thegroup consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.4±0.2, 10.7±0.2,12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2, and 28.0±0.2degrees 2θ. In other such embodiments, the pattern E hydrate has anX-ray powder diffraction pattern comprising five or more peaks selectedfrom the group consisting of 6.2±0.2, 7.8±0.2, 10.2±0.2, 10.4±0.2,10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2, 24.5±0.2,and 28.0±0.2 degrees 2θ.

In some embodiments, the pattern E hydrate has an X-ray powderdiffraction pattern substantially as shown in FIG. 23. The 2θ values forthe peaks in FIG. 23 (and their intensities) are as follows: 6.19 (6),7.81 (18), 10.17 (13), 10.40 (14), 10.68 (39), 12.06 (20), 16.29 (78),19.72 (32), 20.88 (100), 21.77 (27), 24.52 (25), and 28.01 (27).

This invention also relates, in part, to a process for preparing thepattern E hydrate. It was prepared by suspending compound IB-L1-1.1(56.76 mg) in 200 ul THF while heated. Aqueous NaOH (1M, 146 uL, 1.2molar equivalent) was added, which yielded a clear solution. Ethanol(800 ul) was added to the solution. The solution was allowed to coolnaturally to ambient temperatures. Crystals were formed during the slowevaporation process. Although it appears that the lattice canaccommodate as much as one water molecule per molecule of compoundIB-L1-1.1, the recovered pattern D hydrate contained ˜0.25 watermolecules per molecule of compound IB-L1-1.1.

H. Compositions

This invention also is directed, in part, to compositions comprising oneor more compounds and/or salts of the invention (including thecrystalline compounds and salts discussed in section G above). In someembodiments, the compositions comprise one or more substantially phasepure crystalline forms (compounds/salts/solvates/hydrates) discussed insection G above. The compositions can be pharmaceutical compositions.

In some embodiments, the compositions further comprise one or moreadditional therapeutic agents. Such therapeutic agents can, but need notbe, additional HCV inhibitors.

The preferred composition depends on the method of administration, andtypically comprises one or more conventional pharmaceutically acceptablecarriers, adjuvants, and/or vehicles (together referred to as“excipients”). Formulation of drugs is generally discussed in, forexample, Hoover, J., Remington's Pharmaceutical Sciences (MackPublishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and DrugDelivery Systems (Lippincott Williams & Wilkins, 2005).

Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders, and granules. In such solid dosageforms, the compounds or salts are ordinarily combined with one or moreexcipients. If administered per os, the compounds or salts can be mixedwith, for example, lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets cancontain a controlled-release formulation, as can be provided in, forexample, a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsalso can comprise buffering agents, such as sodium citrate, or magnesiumor calcium carbonate or bicarbonate. Tablets and pills additionally canbe prepared with enteric coatings.

Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions (including both oil-in-water andwater-in-oil emulsions), solutions (including both aqueous andnon-aqueous solutions), suspensions (including both aqueous andnon-aqueous suspensions), syrups, and elixirs containing inert diluentscommonly used in the art (e.g., water). Such compositions also cancomprise, for example, wetting, emulsifying, suspending, flavoring(e.g., sweetening), and/or perfuming agents.

Parenteral administration includes subcutaneous injections, intravenousinjections, intramuscular injections, intrasternal injections, andinfusion. Injectable preparations (e.g., sterile injectable aqueous oroleaginous suspensions) can be formulated according to the known artusing suitable dispersing, wetting agents, and/or suspending agents.Acceptable vehicles and solvents include, for example, water,1,3-butanediol, Ringer's solution, isotonic sodium chloride solution,bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids(e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic andnon-ionic detergents), and/or polyethylene glycols.

Formulations for parenteral administration may, for example, be preparedfrom sterile powders or granules having one or more of the excipientsmentioned for use in the formulations for oral administration. Acompound or salt of the invention can be dissolved in water,polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/orvarious buffers. The pH may be adjusted, if necessary, with a suitableacid, base, or buffer.

Suppositories for rectal administration can be prepared by, for example,mixing a compound or salt of the invention with a suitable nonirritatingexcipient that is solid at ordinary temperatures, but liquid at therectal temperature, and will therefore melt in the rectum to release thedrug. Suitable excipients include, for example, cocoa butter; syntheticmono-, di-, or triglycerides, fatty acids, and/or polyethylene glycols.

Topical administration includes the use of transdermal administration,such as transdermal patches or iontophoresis devices.

Other excipients and modes of administration known in the pharmaceuticalart also may be used.

Applicants have discovered that some I-L1 compounds in which R⁶ and thephenyluracil are in trans-position relative to the double bond, when insolution, tend to convert into the corresponding cis-isomer uponexposure to light; thus, it may be desirable to store such solutionsunder conditions that reduce exposure to light (e.g., in an amber bottleor in a dark place).

The preferred total daily dose of the compound or salt (administered insingle or divided doses) is typically from about 0.001 to about 100mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even morepreferably from about 0.01 to about 10 mg/kg (i.e., mg of the compoundor salt per kg body weight). Dosage unit compositions can contain suchamounts or submultiples thereof to make up the daily dose. In manyinstances, the administration of the compound or salt will be repeated aplurality of times. Multiple doses per day typically may be used toincrease the total daily dose, if desired.

Factors affecting the preferred dosage regimen include the type, age,weight, sex, diet, and condition of the patient; the severity of thepathological condition; the severity of the pathological condition; theroute of administration; pharmacological considerations, such as theactivity, efficacy, pharmacokinetic, and toxicology profiles of theparticular compound or salt used; whether a drug delivery system isutilized; and whether the compound or salt is administered as part of adrug combination. Thus, the dosage regimen actually employed can varywidely, and therefore, can derive from the preferred dosage regimen setforth above.

I. Kits

This invention also is directed, in part, to a kit comprising one ormore compounds and/or salts of the in invention. The kit can optionallycontain one or more additional therapeutic agents and/or instructionsfor, for example, using the kit.

J. Methods of Use

This invention also is directed, in part, to a method for inhibitingreplication of an RNA virus. The method comprises exposing the virus toone or more compounds and/or salts of this invention. In someembodiments, replication of the RNA virus is inhibited in vitro. Inother embodiments, replication of the RNA virus is inhibited in vivo. Insome embodiments, the RNA virus whose replication is being inhibited isa single-stranded, positive sense RNA virus. In some such embodiments,the RNA virus whose replication is being inhibited is a virus from theFlaviviridae family. In some such embodiments, the RNA virus whosereplication is being inhibited is HCV.

This invention also is directed, in part, to a method for inhibiting HCVRNA polymerase. The method comprises exposing the polymerase with one ormore compounds and/or salts of this invention. In some embodiments, HCVRNA polymerase activity is inhibited in vitro. In other embodiments, HCVRNA polymerase activity is inhibited in vivo.

The term “inhibiting” means reducing the level of RNA virusreplication/HCV polymerase activity either in vitro or in vivo. Forexample, if a compound/salt of the invention reduces the level of RNAvirus replication by at least about 10% compared to the level of RNAvirus replication before the virus was exposed to the compound/salt,then the compound/salt inhibits RNA virus replication. In someembodiments, the compound/salt can inhibit RNA virus replication by atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, or at least about 95%.

This invention also is directed, in part, to a method for treating adisease that can be treated by inhibiting HCV RNA polymerase. Thus, thisinvention also is directed, in part, to a method for treating hepatitisC in an animal in need of such treatment. These methods compriseadministering to the animal one or more compounds and/or salts of theinvention, and, optionally, one or more additional therapeutic agents.In some embodiments, a therapeutically effective amount of thecompound(s) and/or salt(s) is administered to the animal. “Treating”means ameliorating, suppressing, eradicating, preventing, reducing therisk of, and/or delaying the onset of the disease being treated.Applicants specifically intend that the term “treating” encompassadministration of the compounds and/or salts of the invention to anHCV-negative patient that is a candidate for an organ transplant. Themethods of treatment are particularly suitable for use with humans, butmay be used with other animals, particularly mammals. A“therapeutically-effective amount” or “effective amount” is an amountthat will achieve the goal of treating the targeted condition.

In some embodiments, the methods comprise combination therapy, whereinthe compound(s) and/or salt(s) of the invention is/are co-administeredwith a second (or even a third, fourth, etc.) compound, such as, forexample, another therapeutic agent used to treat hepatitis C (e.g.,interferon or interferon/ribavirin combination, or an HCV inhibitor suchas, for example, an HCV polymerase inhibitor or an HCV proteaseinhibitor). The compound(s) and/or salt(s) of this invention can also beco-administered with therapeutic agents other than therapeutic agentsused to treat hepatitis C (e.g., anti-HIV agents). In theseco-administration embodiments, the compound(s) and/or salt(s) of theinvention and the second, etc. therapeutic agent(s) may be administeredin a substantially simultaneous manner (e.g., or within about 5 minutesof each other), in a sequential manner, or both. It is contemplated thatsuch combination therapies may include administering one therapeuticagent multiple times between the administrations of the other. The timeperiod between the administration of each agent may range from a fewseconds (or less) to several hours or days, and will depend on, forexample, the properties of each composition and active ingredient (e.g.,potency, solubility, bioavailability, half-life, and kinetic profile),as well as the condition of the patient. The compound(s) and/or salt(s)of this invention and the second, etc. therapeutic agent may also beadministered in a single formulation.

This invention also is directed, in part, to a use of one or morecompounds and/or salts of the invention, and, optionally one or moreadditional therapeutic agents to prepare a medicament. In someembodiments, the medicament is for co-administration with one or moreadditional therapeutic agents.

In some embodiments, the medicament is for inhibiting replication of anRNA virus.

In some embodiments, the medicament is for treating hepatitis C.

This invention also is directed, in part, to one or more compoundsand/or salts of the invention, and, optionally one or more additionaltherapeutic agents, for use as a medicament. In some embodiments, themedicament is for inhibiting replication of an RNA virus. In otherembodiments, the medicament is for treating hepatitis C.

K. Intermediate Compounds

This invention also is directed, in part, to intermediates thatcorrespond in structure to formula II that can be used to prepare thecompounds of formula I (and their salts) (although some intermediatescan also be used, just like the compounds of formula I, as HCVinhibitors, and one skilled in the art can determine such ability of thecompounds of formula II by utilizing, for example, the methods discussedbelow):

In formula II:

R¹, R², R³, R⁴, and R⁵ are as discussed above for the compounds offormula I; and

X² is halo.

The various embodiments for

R¹, R², R³, R⁴, and R⁵ (as well as their combinations) discussed aboveapply to the compounds of formula II. As to X², in some embodiments, X²is selected from the group consisting of chloro, bromo, and iodo. Inother embodiments, X² is selected from the group consisting of chloroand bromo. In yet other embodiments, X² is selected from the groupconsisting of chloro and iodo. In yet other embodiments, X² is selectedfrom the group consisting of iodo and bromo. In further embodiments, X²is fluoro. In yet further embodiments, X² is chloro. In yet furtherembodiments, X² is bromo. And in yet further embodiments, X² is iodo.

The various embodiments for

R¹, R², R³, R⁴, R⁵, and X² discussed above can be combined to formvarious embodiments of compounds of formula II, and all embodiments ofcompounds of formula II so formed are within the scope of Applicants'invention. Some exemplary embodiments of the compounds (and saltsthereof) of formula II are discussed below.

In some embodiments, the compounds of formula II correspond in structureto formula IIA:

In other embodiments, the compounds of formula II correspond instructure to formula IIB:

In some embodiments of the compounds of formula II:

R¹ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group;

R² is selected from the group consisting of hydrogen and halo;

R³ is selected from the group consisting of hydrogen and halo;

R⁴ is selected from the group consisting of C₁-C₄-alkyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with up to three        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and    -   (b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl, halo,        and alkylsulfonylamino;

R⁵ is selected from the group consisting of hydrogen, hydroxy, alkyloxy,and halo; and

X² is selected from the group consisting of chloro, bromo, and iodo.

In some embodiments of the compounds of formula II:

is a double carbon-carbon bond;

R¹ is hydrogen;

R² is selected from the group consisting of hydrogen and halo;

R³ is hydrogen;

R⁴ is tert-butyl;

R⁵ is selected from the group consisting of hydrogen, hydroxy, andmethoxy; and

X² is selected from the group consisting of bromo and iodo.

In some embodiments of the compounds of formula II:

R¹ is selected from the group consisting of hydrogen and methyl;

R² is selected from the group consisting of hydrogen and methyl;

R³ is selected from the group consisting of hydrogen and methyl;

R⁴ is tert-butyl;

R⁵ is selected from the group consisting of hydroxy and methoxy; and

X² is selected from the group consisting of chloro, bromo, and iodo.

In some embodiments of the compounds of formula II:

is a double carbon-carbon bond;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

R⁴ is tert-butyl;

R⁵ is selected from the group consisting of hydroxy and methoxy; and

X² is selected from the group consisting of chloro, bromo, and iodo.

In some embodiments, the compound of formula II is selected from thegroup consisting of

The discussion below provides instructions for the preparation ofintermediate compounds of formula II (and salts thereof).

L. Starting Compounds

This invention also is directed, in part, to starting compounds thatcorrespond in structure to formula III that can be used to prepare thecompounds of formulas II and I (and their salts):

In formula III,

R¹, R², and R³ are as discussed above for the compounds of formula I andII. The various embodiments for

R¹, R², and R³ (as well as their combinations) discussed above apply tothe compounds of formula III. The various embodiments for

R¹, R², and R³ discussed above can be combined to form variousembodiments of compounds of formula III, and all embodiments ofcompounds of formula III so formed are within the scope of Applicants'invention. Some exemplary embodiments of the compounds (and saltsthereof) of formula III are discussed below.

In some embodiments of the compounds of formula III:

R¹ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group;

R² is selected from the group consisting of hydrogen and halo; and

R³ is selected from the group consisting of hydrogen and halo.

In some embodiments of the compounds of formula III:

is a double carbon-carbon bond;

R¹ is selected from the group consisting of hydrogen;

R² is selected from the group consisting of hydrogen and halo; and

R³ is selected from the group consisting of hydrogen.

In some embodiments of the compounds of formula III:

R¹ is selected from the group consisting of hydrogen and methyl;

R² is selected from the group consisting of hydrogen and methyl; and

R³ is selected from the group consisting of hydrogen and methyl.

In some embodiments, the compound of formula III is uracil.

This invention also is directed, in part, to starting compounds thatcorrespond in structure to formula IV that can be used to prepare thecompounds of formulas II and I (and their salts):

In formula IV:

R⁴, R⁵, and X² are as discussed above for the compounds of formula I andII; and

X¹ is halo.

The various embodiments for R⁴, R⁵, and X² (as well as theircombinations) discussed above apply to the compounds of formula IV. Asto X¹, in some embodiments, X¹ is selected from the group consisting ofchloro, bromo, and iodo. In other embodiments, X¹ is selected from thegroup consisting of chloro and bromo. In yet other embodiments, X¹ isselected from the group consisting of chloro and iodo. In yet otherembodiments, X¹ is selected from the group consisting of iodo and bromo.In further embodiments, X¹ is fluoro. In yet further embodiments, X¹ ischloro. In yet further embodiments, X¹ is bromo. And in yet furtherembodiments, X¹ is iodo. As to X¹ and X², in some embodiments, X¹ and X²are identical.

The various embodiments for R⁴, R⁵, X¹, and X² discussed above can becombined to form various embodiments of compounds of formula IV, and allembodiments of compounds of formula III so formed are within the scopeof Applicants' invention. Some exemplary embodiments of the compounds(and salts thereof) of formula IV are discussed below.

In some embodiments of the compounds of formula IV:

R⁴ is selected from the group consisting of C₁-C₄-alkyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with up to three        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and    -   (b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl, halo,        and alkylsulfonylamino;

R⁵ is selected from the group consisting of hydrogen, hydroxy, andalkyloxy;

X¹ is selected from the group consisting of chloro, bromo, and iodo; and

X² is selected from the group consisting of chloro, bromo, and iodo.

In some embodiments of the compounds of formula IV:

R⁴ is selected from the group consisting of tert-butyl;

R⁵ is selected from the group consisting of hydrogen, hydroxy, andmethoxy;

X¹ is selected from the group consisting of bromo and iodo; and

X² is selected from the group consisting of bromo and iodo.

In some embodiments of the compounds of formula IV:

R⁴ is selected from the group consisting of tert-butyl;

R⁵ is selected from the group consisting of hydroxy and methoxy;

X¹ is selected from the group consisting of chloro, bromo, and iodo; and

X² is selected from the group consisting of chloro, bromo, and iodo.

In some embodiments of the compounds of formula IV:

R⁴ is tert-butyl;

R⁵ is selected from the group consisting of hydroxy and methoxy;

X¹ is selected from the group consisting of chloro, bromo, and iodo; and

X² is selected from the group consisting of chloro, bromo, and iodo.

In some embodiments, the compound of formula IV is selected from thegroup consisting of

The discussion below provides instructions for the preparation ofstarting compounds of formula IV (and salts thereof).

L. Methods for Preparation

This invention also is directed, in part, to a process for preparingcompounds of formula II. The process comprises reacting a compound offormula III with a compound of formula IV in the presence of (i) copper(I) salt catalyst and (ii) nitrogenous heteroaryl ligand:

In the above process, R¹, R², R³, R⁴, R⁵, X¹, and X² are as discussedabove.

Applicants have discovered that the process generally results in thesubstitution of the N1 hydrogen of uracil derivative compound III thusresulting in intermediate compound II. When X² in intermediate compoundII is chloro, bromo, or iodo, then compound II is suitable forsubsequent reaction (e.g., Suzuki coupling with an appropriate boronicacid or boronate ester) to provide compound of formula I. In otherwords, when X² in intermediate compound II is chloro, bromo, or iodo,the above process is suitable for preparing compounds of formula I aswell.

In some embodiments, compound III is uracil, and compound IV correspondsin structure to a compound selected from the group consisting ofcompound IV-I, IV-Br, and IV-Cl, with compounds IV-I and IV-Br typicallyresulting in better yield than compound IV-Cl.

Suitable Cu(I) catalysts include, for example, CuI, CuBr, CuCl, Cu₂O,and CH₃C(O)OCu. In some embodiments, the catalyst is selected from thegroup consisting of CuI and CuBr. In some such embodiments, the catalystis CuI. In other such embodiments, the catalyst is CuBr.

In some embodiments, the process is conducted in the presence of a base.In some such embodiments, the base is an inorganic base. Suitableinorganic bases include, for example, potassium, sodium, and cesiumsalts (e.g., K₂CO₃, K₃PO₄, Cs₂CO₃, Na₂CO₃). In some embodiments, thebase is selected from the group consisting of potassium salt and cesiumsalt. In some such embodiments, the salt is selected from the groupconsisting of K₃PO₄ and Cs₂CO₃. In some embodiments, the base comprisesa potassium salt. In some such embodiments, the potassium salt is K₂CO₃.In other such embodiments, the potassium salt is K₃PO₄. In someembodiments, the base comprises a cesium salt. In some such embodiments,the potassium salt is Cs₂CO₃.

Typically, the process is conducted in the presence of a solvent.Suitable solvents include, for example, dimethylsulfoxide (DMSO),dimethylformamide (DMF), and acetonitrile (MeCN). In some embodiments,the solvent is DMSO.

Typically, the process is conducted at a temperature of from about 40 toabout 130° C.

In some embodiments, the nitrogenous heteroaryl ligand comprises8-hydroxyquinoline. In other embodiments, the ligand comprises2-(2-pyridyl)-benzimidazole. In yet other embodiments, the ligandcomprises a picolinamide compound corresponding in structure to formulaV:

In formula V, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independentlyselected from the group consisting of hydrogen, C₁₋₄-perfluoroalkyl,C₁₋₄-alkyloxy, C₁₋₄-haloalkyl, chloro, or cyano. In some embodiments,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently selected fromthe group consisting of hydrogen, methyl, methoxy, trifluoromethyl,chloro, and cyano. In some embodiments, the ligand of formula Vcomprises N-(4-cyanophenyl)picolinamide. In other embodiments, theligand of formula V comprises N-(2-cyanophenyl)picolinamide.

In some embodiments, the process comprises (a) preparing a compound offormula IV; and (b) reacting a compound of formula III with a compoundof formula IV in the presense of (i) copper (I) salt catalyst and (ii)nitrogenous heteroaryl ligand, optionally in the presence of inorganicbase.

Compound of formula IV-I can be prepared by, for example, converting2-tert-butylphenol into 2-tert-butyl-4,6-diiodophenol (by, for example,reacting it with NaI and NaOCl), and then converting the2-tert-butyl-4,6-diiodophenol into1-tert-butyl-3,5-diiodo-2-methoxybenzene (by, for example, treating itwith CH₃I in the presence of a base, such as, for example, NaOH).

Compound of formula IV-Br can be prepared by, for example, converting2-tert-butylphenol into 2,4-dibromo-6-tert-butylphenol (by, for example,reacting it with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione), andthen converting the 2,4-dibromo-6-tert-butylphenol into1,5-dibromo-3-tert-butyl-2-methoxybenzene (by, for example, treating itwith CH₃I in the presence of KOtBu).

Additional information about the preparation of compounds of formulas Iand II (and their salts) is provided in the general discussion and/orspecific synthesis examples below. In the discussion below, R¹, R², R³,R⁴, R⁵, L, R^(A), R^(B), R^(C), R^(D), R⁶, R^(E), R^(F), R^(G), R^(H),R^(I), R^(J), R^(K), X¹, and X² have the meaning discussed above unlessotherwise stated.

Compound (1-1), wherein R⁷ is, for example, hydrogen or —CO₂Me, and R⁸is, for example, hydrogen or t-butyl, may be treated with nitric acid insolvents such as, for example, acetic acid or water in a temperaturerange of about 0 to about 35° C. over about 1 to about 5 h to providecompound (1-2). Compound (1-2) may then be reduced using conditionsknown to those skilled in the art to furnish the corresponding aniline(1-3). Typical conditions for this reduction include using hydrogen at apressure of about 1 to about 5 atmospheres in the presence of a catalystsuch as, for example, palladium or platinum on charcoal in a solventsuch as, for example, tetrahydrofuran, ethyl acetate, ethanol, or hexaneat or near ambient temperature over a period of about 1 to about 12 h.Dependent on the functional groups present, an alternative reductionprocedure may be more appropriate such as, for example, using ironpowder in the presence of a mild acid such as, for example, ammoniumchloride or dilute hydrochloric acid at reflux temperatures in a mixtureof solvents containing, for example, methanol, water, and/ortetrahydrofuran over about 1 to about 12 h. Another set of reductionconditions includes the use of sodium borohydride in a solvent mixturesuch as, for example, water and tetrahydrofuran. Yet another set ofreduction conditions includes the use of tin(II) chloride in thepresence of hydrochloric acid in such solvents as, for example, waterand methanol or mixtures thereof.

Compound (1-2) may be modified prior to reduction. For example,treatment of compound (1-2), wherein R⁷ is hydrogen, with iodinemonochloride in a mixture of methanol and water at or near ambienttemperature over a period of about 8 to about 24 h supplies compound(1-4), wherein X¹ is iodine. Alternatively, compound (1-2) can betreated with pyridinium hydrobromide perbromide in a solvent such as,for example, acetic acid at or near ambient temperature over a period ofabout 2 to about 16 h to provide compound (1-4), wherein X¹ is bromine.Modifications may be introduced at the phenol moiety in compound (1-4).For example, the phenol may be alkylated with alkyl halides (e.g.,methyl iodide), alkyl sulfates (e.g., methyl sulfate), alkenyl halides(e.g., allyl bromide), alkynyl halides (e.g., propargyl bromide) in thepresence of a base such as, for example, potassium carbonate in acetone,sodium hydride in dimethylformamide, or potassium t-butoxide intetrahydrofuran, at temperatures from about 0 to about 35° C. over aperiod of about 1 to about 24 h to provide compound (1-5), wherein R⁹is, for example, alkyl, alkenyl, or alkynyl. Alternatively, alkylationmay be achieved by using a reagent such as (trimethylsilyl) diazomethanein solvents such as, for example, methanol or t-butyl methyl ether, ormixtures thereof in a sealed tube at or near room temperature over about8 to about 24 h. Compound (1-5) may subsequently be reduced to compound(1-6) using the iron powder or tin(II) chloride conditions describedabove. An alternative reduction procedure employs hydrogenation atapproximately 1 atmosphere pressure with a catalyst such as 5% platinumon sulfided carbon in a solvent such as methanol. Protection of theresultant aniline of compound (1-6) with, for example, a t-butylcarbamate can be achieved by treatment with di-tert-butyl dicarbonate ina solvent such as, for example, tetrahydrofuran or dioxane at atemperature of about 50 to about 65° C. for about 1 to about 8 hprovides compound (1-7).

Modifications may also occur at the phenol moiety in compound (1-2). Oneskilled in the art may alkylate the phenol of compound (1-2) using, forexample, the conditions described above to obtain compound (1-8).Compound (1-8) is transformed into compound (1-9) using, for example,one or more of the appropriate reduction conditions described above.

Another modification of the phenol group in compound (1-2) issulfonylation to furnish compound (1-8), wherein R⁹ is alkylsulfonyl,carbocyclylsulfonyl, or haloalkylsulfonyl. Such a compound may beprepared by exposing compound (1-2) to sulfonyl chlorides such as, forexample, methanesulfonyl chloride, cyclohexanesulfonyl chloride,benzenesulfonyl chloride, or 3-chloropropane sulfonyl chloride in thepresence of a base such as, for example, triethylamine,diisopropylethylamine, or pyridine in a solvent such as, for example,dichloromethane at or near ambient temperature for a period of about 1to about 24 h. One skilled in the art can then transform compound (1-8)into compound (1-9) with an appropriate set of reduction conditions.

Aniline (2-4) can be prepared through use of the Curtius rearrangement.To this end, compound (2-1), wherein R⁴ is not amino, can be treated inrefluxing thionyl chloride with a catalytic amount of dimethylformamidefor about 1 to about 4 h to obtain acid chloride (2-2). Treatment withthionyl chloride at the reflux temperature in solvents such as, forexample, chloroform or toluene also furnishes compound (2-2). Compound(2-2) can be reacted with an aqueous solution of sodium azide in asolvent such as, for example, acetone over about 1 to about 8 h toprovide acyl azide (2-3). Compound (2-3) can then undergo a Curtiusrearrangement in refluxing solvents such as dioxane or toluene. Theintermediate isocyanate is hydrolyzed with an aqueous acid such asdilute hydrochloric acid in a solvent such as dimethoxyethane to providecompound (2-4).

Compound (3-1), wherein R¹⁰ is, for example, hydrogen, bromine, iodine,or —CO₂Me, can be treated with an acrylic acid either neat at or nearambient temperature in a solvent such as, for example, toluene andheated to reflux over a period of about 15 to about 48 h to supplycompound (3-2). When excess of an acrylic acid is used, compound (3-3)is produced. Compound (3-2) or (3-3) can be treated with urea in asolvent such as, for example, acetic acid at about 100 to about 120° C.over about 2 to about 48 h to supply compound (3-4).

Compound (4-2) can be prepared from compound (3-1) dissolved in solventssuch as, for example, dimethylformamide or dimethylacetamide by theaddition of a benzene solution of (E)-3-methoxyacryloyl isocyanate(prepared as described by Santana, L.; et al. J. Heterocyclic Chem.1999, 36, 293-295.) at a temperature of about −40 to about −15° C. underan inert atmosphere and then warming to ambient temperature for fromabout 30 min to about 4 h. Compound (4-2) can be treated with an acidsuch as, for example, sulfuric acid in mixtures of water and ethanol ina temperature range of from about 90 to about 110° C. for about 1 toabout 8 h to supply compound (4-3). Alternatively, compound (4-2) can becyclized to uracil (4-3) under the basic conditions described by Ueno,Y.; et al. J. Org. Chem. 70:7925-7935 (2005).

Compound (9-1) can be treated in refluxing thionyl chloride for about 1to about 4 h to obtain acid chloride (9-2). Treatment with thionylchloride at the reflux temperature in solvents such as, for example,chloroform or toluene also furnishes compound (9-2). Compound (2) isconverted to the corresponding aldehyde (9-3) by reduction with lithiumtri-t-butoxyaluminum hydride in a solvent such as, for example,tetrahydrofuran at about −78° C. over from about 1 to about 8 h. Thereduction can also be achieved by treatment with indium chloride andtributyltin hydride in the presence of triphenylphosphine in a solventsuch as tetrahydrofuran or toluene at temperatures from about −40 toabout 0° C. Compound (9-3) can be treated with compound (9-4) in thepresence of a base such as potassium t-butoxide in a solvent such asdichloromethane at or near room temperature over a period of about 1 toabout 8 h to provide compound (9-5).

Compound (10-1), wherein X¹ is halo (e.g., bromine, iodine) can undergoa Suzuki reaction with vinyl boronic acid (10-2) to provide compound(10-3). The reaction typically requires the use of a base and acatalyst. Examples of bases include, for example, potassium carbonate,potassium phosphate, potassium t-butoxide, sodium carbonate, cesiumcarbonate, and cesium fluoride. Examples of catalysts include, forexample, tris(dibenzylidineacetone)dipalladium (0), palladium acetate,bis(triphenyl phosphine)palladium (II) chloride,tetrakis(triphenylphosphine)palladium,dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium (II), ordichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct. The reaction may be conducted in a solvent suchas, for example, water, dioxane, dimethoxyethane, dimethylformamide,toluene, ethanol, tetrahydrofuran and the like or mixtures thereof. Thereaction may be conducted at ambient or elevated temperatures.

Compound (11-1) can be converted to compound (11-2) by treatment withdiazomethane in a solvent such as, for example, tetrahydrofuran in thepresence of palladium acetate at or near room temperature over a periodof about 30 min to about 4 h.

Compound (11-1) is reduced to supply compound (14-2). Typical conditionsfor this reduction include using hydrogen at a pressure of about 1 toabout 5 atmospheres in the presence of a catalyst such as, for example,palladium or platinum on charcoal in a solvent such as, for example,tetrahydrofuran, ethyl acetate, ethanol, or hexane at or near ambienttemperature over a period of about 1 to about 12 h.

Compound (15-1) can be converted in a two-step sequence to compound(15-2). The initial step involves reduction of the aromatic nitro moietywith iron powder in the presence of a mild acid such as, for example,ammonium chloride or dilute hydrochloric acid at temperatures from about60 to about 80° C. in a mixture of solvents containing, for example,methanol, water, and tetrahydrofuran over about 1 to about 12 h. Thesecond step consists of exposure of the aniline, prepared in the firststep, to methanesulfonyl chloride in the presence of a base such aspyridine in a solvent such as dichloromethane at or near ambienttemperature.

Compound (17-1) can be mesylated to provide compound (17-2) by treatmentwith methanesulfonyl chloride in the presence of a base such as, forexample, pyridine in a solvent such as, for example, dichloromethane.Compound (17-3) can be exposed to borane dimethyl sulfide complex in asolvent such as, for example, tetrahydrofuran at approximately about 0to about 10° C. to supply compound (17-4). Compounds (17-2) and (17-4)can be combined with acetaldehyde in refluxing tetrahydrofuran.Subsequent treatment with water at room temperature yields compound(17-5).

Carboxylic acid (18-1) can be reduced with boron tetrahydrofuran complexwith heating to provide alcohol (18-2). Compound (18-2) is converted tothe corresponding bromide (18-3) with N-bromosuccinimide andtriphenylphosphine in solvents such as, for example, dichloromethane atroom temperature in several hours. Treatment of compound (18-3) withtriethyl phosphite at about 120° C. for about 1 to about 3 h suppliescompound (18-4). Compound (18-4) can be used for example to makecompound (9-5) as described in Scheme 5.

Benzaldehyde (19-1) can be treated with diethyl phosphonate in thepresence of a base such as, for example, sodium methoxide in a solventsuch as, for example, methanol at room temperature to provide compound(19-2). Compound (19-2) can be treated with N-chlorosuccinimide andtriphenylphosphine in dichloromethane at room temperature to yieldcompound (19-3). Compound (19-2) can also be reacted with(diethylamino)sulfur trifluoride (DAST) to supply compound (19-4).

Compound (19-1) can also be treated with p-toluenesulfonic acid andtrimethyl orthoformate in methanol at about 50° C. to provide acetal(19-5). Compound (19-5) can be converted to compound (19-6) by exposureto triethyl phosphite and boron trifluoride diethyl etherate at about−20° C. to about ambient temperature.

Compounds (19-3), (19-4), and (19-6) can be used for example to makecompound (9-5) as described in Scheme 5.

Phenol (20-1), wherein R⁴ is other than amino, is treated with a sourceof electrophilic halide, such as, for example, iodine monochloride toprovide dihalogenated compound (20-2), wherein X¹ and X² areindependently bromine or iodine. Compound (20-2) is transformed tocompound (20-3) by reaction of an alkylating agent such as, for example,methyl sulfate with a base such as, for example, potassium carbonate inrefluxing acetone. Alternatively, methyl iodide in the presence of abase such as, for example, potassium t-butoxide in a solvent such as,for example, tetrahydrofuran, or dimethylformamide also furnish compound(20-3). In yet another alternative, compound (20-2) can be methylatedwith (trimethylsilyl)diazomethane in a solvent such as, for example,t-butyl methyl ether. Compound (20-3) can be reacted with uracil, ligand(20-4), copper (I) iodide, and potassium phosphate in dimethyl sulfoxideat about 40° C. to about 100° C. to supply compound (20-5).

For example, when in compound (20-3), R⁴ is tert-butyl, X¹ is iodo, andX² is iodo or bromo, compound (20-3) can be stirred with uracil andcompound (20-4) in the presence of CuI and K₂PO₄ in DMSO for about 15 toabout 24 h at about 60° C. to supply compound (20-5). Alternatives toligand (20-4) for making (20-5) are 8-hydroxyquinoline and2-(2-pyridyl)-benzimidazole.

Compound (21-1) can be nitrated with nitric acid in acetic acid in atemperature range of about 10 to about 15° C. to give compound (21-2).The phenol moiety of compound (21-2) can be protected as a silyl ether,e.g. t-butyldimethylsilyl ether, by treatment with a silyl chloride suchas, for example, t-butyl dimethylsilyl chloride and imidazole in asolvent such as, for example, dimethyl formamide at ambient temperatureto furnish compound (21-3). Compound (21-3) may then be reduced usingconditions known to those skilled in the art to furnish thecorresponding aniline (21-4).

Typical conditions for this reduction include using hydrogen at apressure of about 1 to about 5 atmospheres in the presence of a catalystsuch as, for example, palladium or platinum on charcoal in a solventsuch as, for example, tetrahydrofuran, ethyl acetate, ethanol, methanol,or hexane at or near ambient temperature over a period of about 1 toabout 12 h. Dependent on the functional groups present, an alternativereduction procedure may be more appropriate such as, for example, usingiron powder in the presence of a mild acid such as, for example,ammonium chloride or dilute hydrochloric acid at reflux temperatures ina mixture of solvents containing, for example, methanol, water, andtetrahydrofuran over about 1 to about 12 h.

Aniline (21-4) can then by sulfonylated with methanesulfonyl chloride inthe presence of pyridine in a solvent such as, for example,dichloromethane. The starting material and reagents are combined atabout 0° C. and then allowed to gradually warm to ambient temperatureover the course of the reaction to supply compound (21-5). The silylether protecting group is removed under conditions familiar to oneskilled in the art. For example, tetrabutylammonium fluoride intetrahydrofuran at room temperature transforms compound (21-5) tocompound (21-6). The phenol group of compound (21-6) may be sulfonylatedwith trifluoromethanesulfonic anhydride in the presence of a base suchas, for example, pyridine in a solvent such as, for example,dichloromethane at room temperature to provide compound (21-7). Compound(21-7) can be used as described in Scheme 12 to make compound (12-3).

Compound (22-1) is converted to compound (22-2) in a two-step sequence.First, compound (22-1) can be hydrolyzed with a base such as, forexample, sodium hydroxide, lithium hydroxide, or potassium hydroxide ina solvent such as, for example, methanol, ethanol, or tetrahydrofuran,or mixtures thereof. The resultant reaction mixture can be stirred for aperiod of about 6 to about 48 h at ambient temperature. Second, theintermediate carboxylic acid is treated in refluxing thionyl chloridewith or without a catalytic amount of dimethylformamide for about 1 toabout 4 h to deliver acid chloride (22-2). Treatment with thionylchloride at reflux temperature in solvents such as, for example,chloroform or toluene also furnishes compound (22-2). Treatment of thecarboxylic acid with oxalyl chloride in dichloromethane with a catalyticamount of dimethylformamide also furnishes compound (22-2).

Compound (22-2) can be treated with an amine or the corresponding saltin a solvent such as, for example, dioxane, dimethylformamide,dimethylacetamide, or dichloromethane optionally in the presence of abase such as, for example, pyridine, triethylamine ordiisopropylethylamine at temperatures ranging from at or near ambient toabout 100° C. for between about 1 and about 24 h to provide compound(22-4) wherein R¹¹ and R¹² are independently hydrogen or R^(F), or takentogether with the nitrogen to which they are attached form a5-6-membered heterocyclyl or a fused 2-ring heterocyclyl.

Compound (22-2) is converted to the corresponding aldehyde (22-3) byreduction with lithium tri-t-butoxyaluminum hydride in a solvent suchas, for example, tetrahydrofuran at about −60° C. to about −78° C.

Compound (22-3) can be converted to compound (23-2) wherein R¹¹ and R¹²are independently hydrogen or R^(F), or taken together with the nitrogento which they are attached form a 5-6-membered heterocyclyl or a fused2-ring heterocyclyl by treatment with an amine, N(R¹¹)(R¹²), in thepresence of a reductant such as, for example, sodiumtriacetoxyborohydride or sodium cyanoborohydride in a solvent such as,for example, methanol, ethanol, dichloromethane, dimethylacetamide, ordimethylformamide over a period of about 1 to about 24 h. The reactionoften proceeds best at an acidic pH that can be maintained by theaddition of acetic acid or hydrochloric acid.

Compound (22-3) can also be converted to compound (23-3) by reductionwith lithium tri-t-butoxyaluminum hydride in a solvent such astetrahydrofuran at room temperature.

Compound (23-3) can be converted to compound of formula (24-2) bytreatment with thionyl chloride in dichloromethane at room temperature.Compound (24-2) can be treated with a sodium alkoxide, R¹³ONa, in aheated solution of the corresponding alcohol to provide compound (24-3),wherein R¹³ is hydrogen or R^(F).

Compound (25-1) can be brominated by treatment with, for example,pyridinium hydrobromide perbromide in a solvent such as, for example,acetic acid at or near ambient temperature over a period of about 1 toabout 8 h to give compound (25-2). The amino group of compound (25-2)can be removed by exposure to t-butyl nitrite in a solvent such as, forexample, dimethylformamide at a temperature initially at ambienttemperature and then increased to the range of about 50 to about 65° C.to give compound (25-3). Additional aliquots of t-butyl nitrite can beadded at ambient temperature followed by heating until thetransformation is complete. Compound (25-3) can be reduced to compound(25-4) by, for example, treatment with iron and ammonium chloride.

EXAMPLES

The following examples are merely illustrative, and not limiting to thisdisclosure in any way.

Example A Preparation of(E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxyAcrylamide

Part A. Preparation of 2-tert-butyl-4-nitrophenol.

To a vigorously stirred solution of 2-tert-butylphenol (10 g, 66.6 mmol)in heptane (67 ml) was added at a fast drip a solution of 70% nitricacid (4.25 ml, 66.6 mmol) diluted with water (4.25 ml). The resultingdark red/brown mixture was stirred vigorously for 2 h. The suspendedsolid was collected by filtration washed with hexane (300 mL), water(200 mL) and once again with hexane (200 mL) to give a cocoa coloredpowder that was dried to constant mass (4.65 g, 35.6%).

Part B. Preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

To the product from Part A (4.5 g, 23.05 mmol) dissolved in MeOH (120ml) and water (30 mL) was added iodine monochloride (1.155 ml, 23.05mmol) drop wise over a period of 10 min. The mixture was stirred for 2 hand diluted into 1 L of water and allowed to stand overnight. The solidmaterial was collected by filtration and washed 3×50 mL with water anddried under vacuum overnight to give a tan solid (7.14 g, 96%).

Part C. Preparation of 1-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

To an ice bath cooled solution of the product from Part B (5.5 g, 17.13mmol) in MTBE (15 ml) in a 50 mL pressure vessel was added 2.0M TMSdiazomethane (12.85 ml, 25.7 mmol) followed by drop-wise addition ofmethanol (1.0 mL) resulting in calm bubbling. The vessel was sealed andstirred at room temperature for 16 h, cooled and the pressure wasreleased. The solution was partitioned between EtOAc and water. Theorganic layer was washed with 1.0M HCl, saturated potassium carbonatesolution, and saturated NaCl. The organic layer was dried over sodiumsulfate, filtered and concentrated to give a red oil that was usedwithout purification (5.4 g, 84%).

Part D. Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

A mixture of the product from Part C (5.80 g, 17.31 mmol), ammoniumchloride (1.389 g, 26.0 mmol), and iron (4.83 g, 87 mmol) inTHF/MeOH/water (200 mL total, 2/2/1) was refluxed for 2 h, cooled andfiltered through Celite. The filtrate was evaporated and the residue waspartitioned between water and EtOAc. The organic layer was washed withsaturated brine, dried with sodium sulfate, filtered and evaporated togive a brown oil (5.28 g, 100% yield).

Part E. Preparation of(E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxyacrylamide.

To a solution of the product from Part E (3.05 g, 10 mmol) in DMF (50ml) at −20° C. under N₂ was added at a fast drip a 0.4M solution inbenzene of (E)-3-methoxyacryloyl isocyanate (50.0 ml, 20.00 mmol,prepared by the method of Santana et al., J. Heterocyclic Chem. 36:293(1999). The solution was stirred for 15 min at −20° C., warmed to roomtemperature for 45 min and diluted into EtOAc. The EtOAc layer waswashed 4×300 mL with water, 2×100 mL with brine, dried (Na₂SO₄) andconcentrated to a brown solid. The residue was triturated in Et₂O/hexaneto give a fine powder that was collected by filtration and dried to givea tan powder (2.46 g, 57%).

Example B Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

To a suspension of the product from Example A (2.46 g, 5.69 mmol) inethanol (50 ml) was added a solution of 5.5 mL of H₂SO₄ in 50 mL waterand the mixture was heated at 110° C. for 2.5 h to give a clearsolution. The solution was cooled and diluted with 50 mL of water whilestirring to give an off-white solid that was collected by filtration,washed with water and dried (2.06 g, 90%).

Example C Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione

Part A. Preparation of 2-tert-butyl-4,6-diiodophenol.

A solution of 2-tert-butylphenol (20.0 g, 133 mmol) in methanol (266 mL)was treated with sodium hydroxide pellets (6.39 g, 160 mmol). Themixture was stirred until all the sodium hydroxide had dissolved and wasthen cooled in an ice-salt bath to −2° C. Sodium iodide (15.0 g, 100mmol) was added and then 10% sodium hypochlorite solution (45 mL, 73.3mmol) was added drop wise at a rate such that the solution temperaturerose no higher than 1.3° C. This sequence of events was repeated (3×)until a total of 60 g (400 mmol) of sodium iodide had been added and thesodium hypochlorite solution was added until the solution color changedfrom a light green-yellow color to the color of weak iced tea. Thisrequired all but 16 mL of the 180 mL total sodium hypochlorite solutionmeasured out. With continued cooling at ca. 2° C., a solution of sodiumthiosulfate pentahydrate (20 g) in water (100 mL) was added drop wiseover 20 min. After addition, the solution was acidified to pH 3 by dropwise addition of concentrated hydrochloric acid (ca. 35 mL required of40 mL placed in the addition funnel). The precipitate was collected byfiltration and washed with >1 liter of water. The salmon-colored solidwas sucked as dry as possible, and dried in a vacuum oven at 50° C. for18 h. These procedures afforded the product (49.61 g, 93%) as a tansolid.

Part B. Preparation of 1-tert-butyl-3,5-diiodo-2-methoxybenzene.

A solution of the product from Part A (20.0 g, 49.7 mmol) in acetone(140 mL) was treated with methyl iodide (3.9 mL, 8.83 g, 62.2 mmol) and50% (w/w) sodium hydroxide solution (3.02 mL, 4.58 g, 57.2 mmol)followed by stirring at ambient temperature for 48 h. The mixture wasconcentrated in vacuo to a volume of ca. 50-60 mL, followed by dilutionwith heptane (80 mL) and water (50 mL). The layers were separated andthe organic layer was extracted with saturated sodium chloride solution.Drying (Na₂SO₄) and concentration in vacuo afforded the product (20.59g, 99%) as a light yellow oil.

Part C. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

A suspension of the product from Part B (12.04 g, 28.9 mmol), uracil(3.89 g, 34.7 mmol), N-(2-cyanophenyl)picolinamide (1.29 g, 5.79 mmol)and tribasic potassium phosphate (12.9 g, 60.8 mmol) in DMSO (181 mL)was degassed by nitrogen sparge for 1 h. The mixture was then treatedwith copper (I) iodide (551 mg, 2.89 mmol) and degassing was continuedfor another 10 min. The mixture was then warmed at 60° C. for 18 h. Themixture was then poured into water (600 mL) and acidified to pH 3 byaddition of 4N hydrochloric acid solution. The mixture was diluted withethyl acetate, and the organic layer was extracted with water (3×),saturated ammonium chloride solution (1×) and saturated sodium chloridesolution. The solution was dried and treated with (3-mercaptopropyl)silica gel, followed by stirring for 2 h. The mixture was filtered andconcentrated in vacuo. The solid obtained was triturated withether-ethyl acetate (>10:1) and collected by filtration and washed withether. After drying in a vacuum oven at 50° C. for 2 h, these proceduresafforded the product (2.75 g) as a white solid. The mother liquors wereconcentrated in vacuo to afford an amber solid. This material waschromatographed over a Flash 65 silica gel cartridge, eluting with20-100% ethyl acetate in hexanes. These procedures afforded a nearlywhite solid, which was triturated with ether-hexanes and collected byfiltration. After drying in a vacuum oven for 3 h, these proceduresafforded another 4.31 g of the product as a white solid. Total yield:7.06 g (61%).

Example D Preparation of1-(3-tert-Butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione

Part A. Preparation of 2-tert-butyl-4,6-diiodophenol.

2-tert-Butylphenol (99.95 g, 665.36 mmol) was dissolved in 1250 mLmethanol and converted to the corresponding phenoxide with 31.96 g(799.0 mmol, 1.2 equiv.) of sodium hydroxide by stirring the sodiumhydroxide pellets at room temperature, and then cooling the reactionmixture in an ice/salt bath. Sodium iodide (299.34 g, 1997.07 mmol, 3.0equiv.) and 8.3% bleach (1265.83 g, 1411.39 mmol, 2.1 equiv.) were addedto the cold reaction solution in four equal portions, the bleach beingadded while keeping the reaction mixture at <0° C. 500 mL of 20% (w/w)sodium thiosulfate solution was added over an 18-minute period, with thetemperature rising from −0.6° C. to 2.5° C. The pH of the reactionmixture was adjusted to approximately 3 by adding 197.5 mL of conc. HClover a period of 97 min with the reaction temperature going from 1.2° C.to 4.1° C. The resulting slurry was filtered, and the wet cake washedwith ˜2 L of water. The wet cake was left on the Buchner funnel undervacuum overnight (approximately 15 h) to yield 289.33 g (potencyadjusted yield=254.61 g) of the title product.

Part B. Preparation of 1-tert-butyl-3,5-diiodo-2-methoxybenzene.

The product from Part A (93% assay, 21.6 g, 50 mmol) was dissolved in140 mL of acetone. Methyl iodide (4.2 mL, 67.5 mmol, 1.35 equiv.) wasadded, followed by 50% aqueous sodium hydroxide (5.0 g, 62.5 mmol, 1.25equiv.). The reaction was stirred overnight, then concentrated toapproximately 50-60 mL. 80 mL of heptanes was added followed by 50 mL ofwater, and the layers were shaken and separated, and the aqueous layerwas back extracted with 20 mL of heptanes. The organic layers werecombined and washed twice with 50 mL each of 10% aqueous NaCl to afford91.1 grams of a heptane solution, which assayed to 19.1 g of the titlecompound.

Part C. Preparation of1-(3-tert-Butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

Uracil (33.3 g, 297 mmol, 1.2 equiv.), K₃PO₄ (106 g, 500 mmol, 2.1equiv.), CuI (4.6 g, 24.2 mmol, 0.1 equiv.), andN-(2-cyanophenyl)picolinamide (6.4 g, 28.7 mmol, 0.12 equiv.) werecharged to a flask and inerted with argon. The1-tert-butyl-3,5-diiodo-2-methoxybenzene was solvent switched into MeCN,dissolved in 1 L DMSO and sparged with argon and added to the solids.The reaction was heated to 60° C. for 16 h. After cooling, the reactionwas diluted with 2 L EtOAc and washed with 2.6 L water (back extractedwith 3×1 L EtOAc). The combined organic layers were washed with 2×1 L of0.25M (CuOAc)₂ then 2×830 mL 15% NH₄Cl then 800 mL brine. The organiclayer was then concentrated and chased with 1 L heptane, then trituratedwith refluxing 85:15 (v/v) heptane:iPrOAc for 4 h. After cooling, theproduct was collected by filtration and washed with an additional 330 mLof 85:15 v/v heptanes:EtOAc to yield after drying 66.9 g (70% yield) ofthe product as a white solid.

Example E Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide

The boronic acid (96% potency) (3.75 g, 15.6 mmol, 1.2 eq), product fromExample D (5.0 g, 12.5 mmol), Cytec ligand (175 mg, 5 mol %), Pd2(dba)3(46 mg, 0.4 mol %) and potassium phosphate (5.25 g, 25.0 mmol, 2 eq.)were charged to a 3 neck RB flask. The solids were purged with nitrogenfor 10 min. 75 mL 4:1 THF:water was sparged 10 min and charged to theflask. The mixture was stirred to dissolve the solids followed byheating the mixture at 50° C. in darkness overnight. HPLC showed thereaction was not complete after stirring overnight (˜2% iodouracilremained). The reaction mixture was diluted with 375 mL DCM and 250 ml10% citric acid. The mixture was shaken in a sep funnel and the layerswere separated. The DCM layer was washed with a solution of 0.6 gL-cysteine in 250 ml 5% NaHCO₃ for 30 min which changed the DCM layercolor from orange to yellow. Repeated the 0.6 g L-cysteine in 250 ml 5%NaHCO₃ for 30 min treatment followed by a 250 ml 5% NaHCO₃ wash, and a250 ml 10% NaCl wash. The DCM layer was treated with 2 gm thioureasilica for 30 min. Added 1 gm carbon to decolorize mixed 5 min andfiltered through hy-flo. The wet cake was washed with DCM. The DCMsolution was then stripped to give 6.74 g of a light yellow solid. Thesolids were ˜92% pure. The solids were heated in a mixture of 192 ml DCMand 9 mL MeOH. They never completely dissolved. Cooled to room temp withmixing. 80 ml heptane was added and more product began to crystallize.The slurry stirred over the weekend. Added 50 ml heptane in portionsuntil a total of 230 ml heptane was added. The product was filtered.Filtrate was measured at 1.21 mg/mL at 210 nm and 1.35 at 220 nm, whichequals a 522-582 mg loss in the liquors or 9-10% loss vs. theoretical.The wet cake was washed with 50 ml of a 27 ml Heptane:22 ml DCM: 1 mlMeOH mixture. The wash contained 0.5 mg/mL product or 25 mg (0.4% vs.theoretical). Product yield 5.22 gm (88.9%), purity 99.2% PA. Iodouracilwas removed in the crystallization. Samples were submitted to solidstate for analysis and analytical for Pd determination. NMR did not showany residual solvent.

Example 1 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IA-L1-1.9

Part A. Preparation of methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate.

Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28.66 g, 108.4 mmol) wasdissolved with stirring in 430 mL glacial acetic acid and the resultingmixture was treated drop wise with fuming nitric acid (90%, 179.26 mL).When the addition was complete, the resulting mixture was stirred for2.5 h. The reaction mixture was poured into a 2.0 L of crushed ice andallowed to stand 30 min. Afterwards, 1.0 L of water was added and theice water mixture was allowed to melt. The mixture was then filtered,washed with water and dried to provide the title compound (240.57 g,89%).

Part B. Preparation of methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate.

Methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate (11.41 g, 45.0 mmol),potassium carbonate (9.34 g, 67.6 mmol), acetone (200 mL), and dimethylsulfate (6.46 g, 67.6 mmol) were added together. The resultant mixturewas then heated to reflux for 16 h. The mixture was then filtered andthe solid was washed with ethyl acetate. The resulting organic liquidwas then concentrated under vacuum to an oil and redissolved in ethylacetate (600 mL). The organic solution was then washed with water,dried, filtered and concentrated under vacuum to an oil that was thensubjected to purification via column chromatography (gradient of 5% to40% EtOAc/Hexanes) to yield the title compound as an oil (10.42, 87%).

Part C. Preparation of methyl 5-amino-3-tert-butyl-2-methoxybenzoate.

Methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate (10.42 g, 39.0 mmol), ironpowder (325 mesh, 10.89 g, 195 mmol), ammonium chloride (3.13 g, 58.5mmol), water (30 mL), and methanol (150 mL) were added together. Theresultant mixture was then refluxed for 1 h. The mixture was then cooledto room temperature, filtered through celite, and the celite washed withmethanol. The filtrate was then concentrated under vacuum and dissolvedin ethyl acetate (600 mL). The resultant solution was then washed withwater and brine. The organic extract was then dried, filtered andconcentrated under vacuum to yield the title compound as an oil (9.25 g,100%).

Part D. Preparation of3-(3-tert-butyl-4-methoxy-5-(methoxycarbonyl)phenylamino)propanoic acid.

The product from Part C (16.44 g, 69.3 mmol) was dissolved in toluene(200 mL). This mixture was heated to reflux and acrylic acid added overtime (1 mL of acrylic acid added every 3 h, 5.23 mL total, 76.2 mmol).The mixture was then refluxed for 24 h. The mixture was then cooled andconcentrated under vacuum to dryness to yield an oil as the crude titlecompound that was used directly in the next reaction.

Part E. Preparation of methyl3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

The product from Part D (21.43 g, 69.3 mmol), urea (10.4 g, 173 mmol)and acetic acid (glacial, 200 mL) were added together. The mixture wasthen heated to 120° C. for 18.5 h followed by concentration under vacuumto give an oil. To this oil was added methanol (13 mL), and ethylacetate (350 mL). The resultant mixture was allowed to stand for 24-48 hwhereby a precipitate formed. The resulting solid was filtered off andwashed with a small amount of methanol (10 mL) and then air dried toyield the title compound as a solid (15.26 g, 66%).

Part F. Preparation of3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxy benzoicacid.

The product from Part D (4.52 g, 13.52 mmol), methanol (70 mL), andtetrahydrofuran (70 mL) were added together. The mixture was thenstirred vigorously until a homogenous solution resulted. Oncehomogenous, a solution of aqueous sodium hydroxide (1.0M, 68 mL) wasadded. The mixture was then stirred for 12 h, the mixture was thenconcentrated under vacuum to remove the organic solvent, followed by theaddition of aqueous hydrochloric acid (1.0M, 80 mL) that resulted insolid formation. The mixture was then concentrated under vacuum. To thismaterial was added hydrochloric acid (12M, 100 mL) and the resultantmaterial heated to 100° C. for 1.5 h. The reaction was then cooled andwater added. The resulting solid was filtered, washed with water, anddried to yield the title compound as a solid (3.55 g, 82%).

Part G. Preparation of3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxy-benzaldehyde.

The product obtained in Part F (4.07 g, 12.71 mmol) and thionyl chloride(40.82 mL, 559 mmol) were combined and the mixture was refluxed for 2 h,followed by concentration under vacuum to provide a light yellow coloredsolid product. The solid was dissolved in tetrahydrofuran (125 mL), thesolution cooled to −78° C. and LiAlH(OtBu)₃ (1M, 14 mL) was added slowlyover 10 min while maintaining the temperature at −78° C. The mixture wasstirred at −78° C. for 2 h, and the reaction was quenched withhydrochloric acid (aq., 1M, 25 mL) at −78° C. The mixture was warmed toroom temperature and ethyl acetate was added. The layers were separatedand the aqueous layer was washed with ethyl acetate. The organicextracts were combined and washed with half saturated sodium bicarbonatesolution. The organic layer was dried, filtered and concentrated undervacuum to yield the title compound as a solid (3.73 g, 96%).

Part H. Preparation of1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydro-pyrimidine-2,4(1H,3H)-dione.

The product prepared in Part G (1.00 g, 3.29 mmol) and diethyl4-nitrobenzyl-phosphonate (0.853 g, 3.12 mmol) were dissolved indichloromethane (50 mL). Solid potassium tert-butoxide (0.737 g, 6.57mmol) was added portion wise at room temperature. The resultant dark redsolution was stirred for 1.5 h at room temperature. 1N aqueous HCl (50mL) solution was added and the mixture was stirred 30 min, and thendiluted with dichloromethane (50 mL). The resultant organic layer wasseparated and dried. The material was purified by column chromatographyon silica gel using 99/1 dichloromethane/methanol as eluent to obtainthe title compound as a solid (1.12 g, 80%).

Part I. Preparation of Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

The product obtained in Part H (1.1 g, 2.60 mmol), iron (0.725 g, 12.99mmol), and ammonium chloride (0.208 g, 3.90 mmol) was added to a mixtureof tetrahydrofuran (40 mL), ethanol (40 mL) and water (12 mL). Theslurry was heated to 90° C. for 45 min, and then cooled to ambienttemperature. The solution was filtered through a pad of celite (10 g),washed with ethanol (20 mL), and the filtrate concentrated under vacuumto a solid. The resulting solid was dissolved in ethyl acetate (100 mL),and the solution was washed with water (50 mL) and dried over Na₂SO₄.The drying agent was filtered off and the solvent removed under vacuumto give the aniline adduct as a yellow solid (830 mg).

The solid (830 mg, 2.109 mmol) was dissolved in dichloromethane (50 mL),and pyridine (0.512 mL, 6.33 mmol) and methanesulfonyl chloride (0.181mL, 2.32 mmol) were added and the resulting solution was stirred at roomtemperature 16 h. Dichloromethane (100 mL) was added followed byextraction with a 1N aq. HCl solution (2×50 mL). The organic layer wasdried, concentrated under vacuum and purified by column chromatographyon silica gel using 98/2 CH₂Cl₂/MeOH to provide the title compound as asolid (480 mg, 39%, two steps). m.p.=260-261° C. (trans-isomer) ¹H NMR(500 MHz, DMSO-d₆): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.7 Hz, 2H), 3.01 (s,3H), 3.75 (s, 3H), 3.79 (t, J=6.6 Hz, 2H), 7.13 (d, J=16.5 Hz, 1H), 7.15(d, J=2.4 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.25 (d, J=16.5 Hz, 1H), 7.51(d, J=2.4 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 9.80 (bs, 1H), 10.30 (s, 1H).(trans-isomer).

Example 2 Preparation of(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-chlorovinyl)phenyl)methanesulfonamideCompound IA-L1-1.3

Part A. Preparation of diethyl hydroxy(4-nitrophenyl)methylphosphonate.

The title compound was prepared as described in Taylor, W P, et. Al,Bioorg. Med. Chem. 4:1515-1520 (1996). 4-Nitrobenzaldehyde (3.0 g, 19.85mmol) and diethyl phosphonate (2.74 g, 19.85 mmol) were combined andtreated with a 0.5N solution of sodium methoxide in methanol (0.993 mL,0.496 mmol). The resulting red-orange solution was stirred 12 h at roomtemperature. The reaction mixture was extracted with dichloromethane (20mL) followed by half saturated ammonium chloride (20 mL). The organiclayer was separated, dried and concentrated under vacuum to provide thetitle compound as a semi-solid (5.1 g, 89%).

Part B. Preparation of diethyl chloro(4-nitrophenyl)methylphosphonate.

The product prepared in Part A (500 mg, 1.729 mmol) was dissolved indichloromethane (10 mL) and treated with triphenylphosphine (998 mg,3.80 mmol), followed by N-chlorosuccinimide (462 mg, 3.46 mmol). Themixture was stirred at room temperature for 18 h. The solution wasconcentrated under vacuum and the residue was purified by columnchromatography using silica gel eluting with a 1/1 mixture ofhexanes/ethyl acetate to provide the title compound as an oil (262 mg,49%).

Part C. Preparation of(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-chlorovinyl)phenyl)methanesulfonamide.

The product prepared in Example 1, Part G (100 mg, 0.329 mmole) wastreated with the product obtained from Part B using the proceduresdescribed in Example 1, Part H and Example 1, Part I to provide 39 mg ofthe title compound. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 1.36 (s, 9H), 2.71(t, J=6.8 Hz, 2H), 3.06 (s, 3H), 3.71 (s, 3H), 3.78 (t, J=6.8 Hz, 2H),7.23 (d, J=2.6 Hz, 1H), 7.27 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.48 (d,J=2.6 Hz, 1H), 7.78 d, J=8.8 Hz, 1H), 10.05 (s, 1H), 10.34 (s, 1H).

Example 3 Preparation of(E)-1-(3-tert-butyl-5-(4-fluorostyryl)-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione Compound IA-L1-1.12

The title compound was prepared according the procedures described inExample 1, Part H and Example 1, Part I using the product obtained inExample 1, Part G (50 mg, 0.164 mmol) and diethyl4-fluorobenzylphosphonate (40.5 mg, 0.164 mmol). The title compound wasobtained as a solid (30 mg, 46%). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 1.37(s, 9H), 2.72 (t, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.79 (t, =6.6 Hz, 2H),7.21 (m, 4H), 7.30 (d, J=16.3 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 7.73 (m,2H), 10.35 (s, 1H).

Example 4 Preparation of(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluorovinyl)phenyl)methanesulfonamideCompound IA-L1-1.4

Part A. Preparation of diethyl fluoro(4-nitrophenyl)methylphosphonate.

The title compound was prepared as described in Taylor, W P, et. Al,Bioorg. Med. Chem. 4:1515-1520 (1996). The product from Example 2, PartA (500 mg, 1.729 mmol) was dissolved in dichloromethane (10 mL) andtreated by drop wise addition of (diethylamino)sulfur trifluoride (DAST)(2.5 mL, 18.9 mmol). The mixture was stirred at room temperature for 18h. A solution of half saturated sodium phosphate monobasic (20 mL) wasadded followed by dichloromethane (20 mL) addition and separation of theresulting organic phase. The organic solution was dried and concentratedunder vacuum, and then subjected to column chromatography using silicagel eluting with a 1/1 mixture of hexanes/ethyl acetate to provide thetitle compound as an oil (215 mg, 43%).

Part B. Preparation of(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluorovinyl)phenyl)methanesulfonamide.

The product prepared as described in Part A (100 mg, 0.329 mmole) wastreated with the product prepared in Example 1, Part G (96 mg, 0.329mmole) according to the procedures described in Example 1, Part H andExample 1, Part I to provide 53 mg of the title compound as a 1/1mixture of cis/trans isomers. Reverse phase HPLC chromatographicseparation using a 40-100% gradient of acetonitrile in 0.1% aqueoustrifluoroacetic acid provided the title compound as a solid (20 mg). ¹HNMR (300 MHz, DMSO-d₆): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.8 Hz, 2H), 3.06(s, 3H), 3.77 (s, 3H), 3.78 (m, 2H), 6.62 (d, J=40.4 Hz, 1H), 7.18 (d,J=2.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.55 (d, J=2.6 Hz, 1H), 7.75 (d,J=8.8 Hz, 2H), 10.08 (s, 1H), 10.33 (s, 1H).

Example 5 Preparation of(E)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluorovinyl)phenyl)methanesulfonamideCompound IA-L1-1.5

Reverse phase HPLC chromatographic separation of the 1/1 mixture ofcis/trans isomeric material (53 mg) from Example 4, Part A using a40-100% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acidprovided the title compound as a solid (16.5 mg). ¹H NMR (300 MHz,DMSO-d₆): δ ppm 1.33 (s, 9H), 2.60 (t, J=6.6 Hz, 2H), 3.01 (s, 3H), 3.57(t, J=6.6 Hz, 2H) 3.79 (s, 3H), 6.46 (d, J=21.3 Hz, 1H), 6.87 (d, J=2.2Hz, 1H), 7.14 (m, 3H), 7.36 (d, J=8.8 Hz, 2H), 10.02 (s, 1H), 10.24 (s,1H).

Example 6 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxystyryl)-2-fluorophenyl)methanesulfonamideCompound IA-L1-1.26

Part A. Preparation of 4-(bromomethyl)-2-fluoro-1-nitrobenzene.

(3-Fluoro-4-nitrophenol)methanol (1.24 g, 7.25 mmol) was dissolved indichloromethane (25 mL) and treated with triphenylphosphine (2.281 g,8.70 mmol) followed by N-bromosuccinimide (1.548 g, 8.70 mmol). Themixture was stirred at room temperature for 2 h. Water (50 mL) anddichloromethane (40 mL) were added, and the organic layer was separatedand dried. The solution was concentrated under vacuum and purified bycolumn chromatography using silica gel eluting with a 5/1 mixture ofhexanes/ethyl acetate to provide the title compound as a solid (1.27 g,75%).

Part B. Preparation of diethyl 3-fluoro-4-nitrobenzylphosphonate.

The product prepared in Part A (1.27 g, 5.43 mmol) was added to triethylphosphite (8 mL, 54.3 mmol) and the solution heated to 120° C. for 1 hr.After cooling, the excess triethyl phosphite was removed by heatingunder vacuum and the residue subjected to column chromatography onsilica gel using 99/1 dichloromethane/methanol as eluent to obtain thecrude title compound as an oil (800 mg).

Part C. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxystyryl)-2-fluorophenyl)methanesulfonamide.

The product described in Example 1, Part G (533 mg, 1.751 mmole) wastreated with the product described in Part B (510 mg, 1.751 mmole)according to the procedures described in Example 1, Part H and Example1, Part I to provide 80 mg of the title compound. ¹H NMR (300 MHz,DMSO-d₆): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.5 Hz, 2H), 3.05 (s, 3H), 3.76(s, 3H), 3.79 (t, J=6.6 Hz, 2H), 7.18 (m, 2H), 7.36 (d, J=16.5 Hz, 1H),7.39 (m, 1H), 7.44 (m, 1H), 7.52 (d, J=2.6 Hz, 1H), 7.63 (m, 1H), 9.65(s, 1H), 10.35 (s, 1H).

Example 7 Preparation ofN-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)cyclopropyl)phenyl)methanesulfonamideCompound IA-L8-1.1

The product obtained as described in Example 1, Part I (30 mg, 0.064mmol) was dissolved in tetrahydrofuran (2 mL) and treated with 0.95 mLof a 0.67M ether solution of diazomethane (0.636 mmol) followed bypalladium acetate (0.7 mg, 0.0031 mmol). The mixture was stirred for 30min at room temperature followed by removal of the solid by filtrationand concentration of the filtrate. The filtrate was purified by columnchromatography on silica gel using 98/2 dichloromethane/methanol aseluent to obtain the title compound as a solid (21.6 mg, 70%). m.p.265-266° C. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 1.33 (s, 9H) 1.50 (m, 2H),2.13 (m, 1H), 2.27 (m, 1H), 2.69 (t, J=6.6 Hz, 2H), 2.94 (s, 3H), 3.63(s, 3H), 3.74 (t, J=6.6 Hz, 2H), 6.84 (d, J=2.6 Hz, 1H), 7.04 (d, J=2.6Hz, 1H), 7.14 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 9.60 (s, 1H),10.29 (s, 1H).

Example 8 Preparation ofN-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)phenyl)methanesulfonamideCompound IA-L5-2-1.1

The product obtained as described in Example 1, Part I (415 mg, 0.88mmol) was dissolved in methanol (30 mL) and treated with 50 mg of 10%palladium on carbon. The slurry was stirred for 48 h at room temperatureunder 1 atm of hydrogen. The reaction mixture was filtered throughcelite and concentrated in vacuo to provide the title compound as asolid (230 mg, 55%). m.p. 233-234° C. ¹H NMR (300 MHz, DMSO-d₆): δ ppm1.34 (s, 9H), 2.68 (t, J=6.8 Hz, 2H), 2.86 (s, 4H), 2.93 (s, 3H), 3.70(m, 2H), 3.74 (s, 3H), 7.11 (m, 4H), 7.23 (m, 2H), 9.59 (s, 1H), 10.29(s,).

Example 9 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)styryl)phenyl)methanesulfonamideCompound IA-L1-1.16

Part A. Preparation of methyl 3-tert-butyl-5-(chlorocarbonyl)benzoate.

A mixture of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (9.18 g, 38.9mmol, prepared by the method of Carter et. al., WO2005021500A1), thionylchloride (75 mL) and 1 drop of DMF in toluene (200 mL) was heated atreflux for 2 h, cooled and concentrated. The residue was azeotroped withtoluene (3×50 mL) and dried under high vacuum to give the title compoundas an off-white waxy solid (9.9 g, quantitative yield).

Part B. Preparation of methyl 3-(azidocarbonyl)-5-tert-butylbenzoate.

To the product of Part A (9.9 g, 38.9 mmol) in acetone (200 ml) wasadded at a fast drip a solution of sodium azide (10.12 g, 156 mmol)dissolved in water (20 mL). The mixture was stirred for 2 h and dilutedwith EtOAc. The organic layer was washed with H₂O, saturated brine,dried (Na₂SO₄), filtered and concentrated to give the title compound asa white solid (9.9 g, 97%).

Part C. Preparation of methyl 3-amino-5-tert-butylbenzoate.

The product from Part B (9.9 g, 37.9 mmol) in toluene (100 mL) washeated at reflux for 1 h and concentrated to give the intermediateisocyanate which was dissolved in DME (60 mL) treated with 8% HCl (150mL) and stirred for 16 h. The mixture was concentrated and the residuewas dissolved in water, neutralized with solid sodium bicarbonate andextracted 3×100 mL with EtOAc. The organics were combined, washed withsaturated NaCl, dried (Na₂SO₄), filtered and concentrated. The crudeproduct was chromatographed on silica eluting with 2:1 hexane/EtOAc togive the title compound as an oil (2.7 g, 35%).

Part D. Preparation of methyl3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

A mixture of the product of Part C (2.34 g, 11.29 mmol) and acrylic acid(2.32 ml, 33.9 mmol) in toluene (60 ml) was heated at reflux undernitrogen for 24 h, cooled and concentrated. The resulting residue wasthen treated with urea (2.03 g, 33.9 mmol) in acetic acid (35 ml) andheated at 120° C. for 24 h, cooled and concentrated. The residue wasazeotroped 3×50 mL with toluene and dissolved in 100 mL of EtOAc. Theorganic layer was washed with dilute aqueous NaHCO₃, H₂O, saturatedbrine, dried (Na₂SO₄), filtered and concentrated to give the titlecompound as a white solid (2.1 g, 61%).

Part E. Preparation of3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid.

A mixture of the product from Part D (1.8 g, 5.91 mmol) and 1M NaOH(29.6 ml, 29.6 mmol) in MeOH (15 ml) and THF (15 mL) was stirred for 24h and concentrated. The residue was treated with 50 mL of 1M HCl andextracted into EtOAc. The EtOAc layer was washed with H₂O, saturatedbrine, dried (Na₂SO₄), filtered and concentrated to give a white solid.This intermediate urea was combined with 20 mL of concentrated HCl andheated at 100° C. for 1 h, cooled and diluted with 75 mL of ice water togive a white powder which was collected by filtration and dried toconstant mass to give the title compound (1.6 g, 93%).

Part F. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)styryl)phenyl)methanesulfonamide.

The product described in Part E was treated with thionyl chloride andlithium tri-tert-butoxyaluminum hydride according to proceduresdescribed in Example 1, Part G to produce3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzaldehyde. Thealdehyde was treated with diethyl 4-nitrobenzylphosphonate according theprocedures described in Example 1, Part H and Example 1, Part I toprovide the title compound (85 mg). ¹H NMR (300 MHz, DMSO-d₆): δ ppm1.32 (s, 9H) 2.72 (t, J=6.43 Hz, 2H) 3.01 (s, 3H) 3.82 (t, J=6.62 Hz,2H) 7.18-7.25 (m, 5H) 7.39 (s, 1H) 7.46 (s, 1H) 7.58 (d, J=8.46 Hz, 2H)9.84 (s, 1H) 10.37 (s, 1H).

Example 10 Preparation of(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-methoxyvinyl)phenyl)methanesulfonamideCompound IA-L1-1.17

Part A. Preparation of 1-(dimethoxymethyl)-4-nitrobenzene.

A flask equipped with a magnetic stir bar and vigreux column was chargedwith 4-nitro-benzaldehyde (5.0 g, 33.1 mmol), pyridiniump-toluenesulfonate (1.66 g, 6.62 mmol), trimethoxymethane (3.51 g, 33.1mmol) and methanol (100 mL). The mixture was heated at 50° C. for 12 hand was concentrated in vacuo. The residue was redissolved in EtOAc andwashed with aq. NaOH (1 M), H₂O and brine. The mixture was dried(Na₂SO₄), filtered and concentrated in vacuo to yield the title compoundas a clear, light yellow oily product (6.36 g, 97%).

Part B. Preparation of diethyl methoxy(4-nitrophenyl)methylphosphonate.

The product from Part A (3.0 g, 15.2 mmol) and triethyl phosphite (2.53g, 15.2 mmol) were dissolved in dichloromethane (30 mL) under a nitrogenatmosphere, cooled to −20° C. and treated with drop wise addition ofboron trifluoride etherate (2.27 g, 16 mmol). The mixture was allowed toslowly warm to room temperature overnight with stirring. Water was addedand the resulting mixture was stirred 5 min, separated and the organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo to a solidresidue. The residue was purified on silica gel (100% EtOAc to 3%CH₃OH/EtOAc) to yield the title compound as a light yellow oily product(3.78 g, 82%).

Part C. Preparation of(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-methoxyvinyl)phenyl)methanesulfonamide.

The product obtained according to the procedure described in Example 1,Part G (400 mg, 1.314 mmole) was treated with the product obtained inPart B (399 mg, 1.314 mmole) according to the procedures described inExample 1, Part H and Example 1, Part I to provide the title compound(17 mg, 6%). ¹H NMR (300 MHz, DMSO-d₆):

ppm 1.36 (s, 9H) 2.71 (t, J=6.62 Hz, 2H) 3.05 (s, 3H) 3.58 (s, 3H) 3.75(s, 3H) 3.76-3.81 (m, 2H) 6.25 (s, 1H) 7.11 (d, J=2.57 Hz, 1H) 7.27 (d,J=8.46 Hz, 2H) 7.60 (d, J=8.82 Hz, 2H) 7.67 (d, J=2.57 Hz, 1H) 9.96 (s,1H) 10.32 (s, 1H).

Example 11 Preparation of(E)-1-(3-tert-butyl-4-methoxy-5-styrylphenyl)dihydro-pyrimidine-2,4(1H,3H)-dioneCompound IA-L1-1.18

The product obtained according to procedure described in Example 1, PartG (50 mg, 0.164 mmole) was treated with diethyl benzylphosphonate (0.034ml, 0.164 mmole) according to the procedure described in Example 1, PartH to provide the title compound (13 mg, 19%). ¹H NMR (300 MHz, DMSO-d₆):δ ppm 1.37 (s, 9H) 2.72 (t, J=6.62 Hz, 2H) 3.76 (s, 3H) 3.80 (t, J=6.80Hz, 2H) 7.16-7.18 (m, 1H) 7.21-7.23 (m, 1H) 7.29-7.33 (m, 2H) 7.36-7.43(m, 2H) 7.54 (d, J=2.57 Hz, 1H) 7.64 (d, J=7.35 Hz, 2H) 10.35 (s, 1H).

Example 12 Preparation of(E)-1-(3-tert-butyl-4-methoxy-5-(4-methoxystyryl)phenyl)dihydropyrimidine-2,4(1H,3H)-dioneCompound IA-L1-1.14

The product obtained according to procedure described in Example 1, PartG (50 mg, 0.164 mmole) was treated with diethyl4-methoxybenzylphosphonate (0.028 ml, 0.164 mmole) according to theprocedure described in Example 1, Part H to provide the title compound(4 mg, 4%). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 1.37 (s, 9H) 2.71 (t,J=6.62 Hz, 2H) 3.70-3.81 (m, 8H) 6.96 (d, J=8.82 Hz, 2 H) 7.13 (d,J=2.21 Hz, 1H) 7.15 (d, J=2.57 Hz, 2H) 7.50 (d, J=2.57 Hz, 1H) 7.58 (d,J=8.46 Hz, 2H) 10.34 (s, 1H).

Example 13A Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.1

Part A. Preparation of (E)-methyl3-tert-butyl-2-methoxy-5-(3-(3-methoxyacryloyl)ureido)benzoate.

The product obtained as described in Example 1, Part C (2.0 g, 8.43mmol) was dissolved in 30 mL of N,N-dimethylacetamide and cooled to −25°C. A 0.5 Molar solution of E-3-methoxyacryloyl isocyanate in benzene(21.9 mL, 10.96 mmol) was added drop wise and the resulting solution wasstirred at ambient temperature for 4 h, and then poured into water. Theproduct was extracted into dichloromethane, washed with brine, driedover sodium sulfate, filtered and evaporated under vacuum to give thetitle compound.

Part B. Preparation of methyl3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

The product from Part A (3.1 g, 8.51 mmol) was dissolved in ethanol (60mL). To this solution was added a mixture of concentrated sulfuric acid(6 mL) and water (60 mL). The heterogeneous mixture was heated at 100°C. for 3 h. The ethanol was removed under vacuum, and then the aqueoussolution was extracted with dichloromethane and evaporated to dryness.This residue was purified by column chromatography on silica gel,eluting with 1% methanol/dichloromethane to yield the title compound(1.23 g, 44%).

Part C. Preparation of3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzoic acid.

The product from Part B (1.23 g, 3.7 mmol) was taken up in ethanol (5mL) and 1M sodium hydroxide solution (10 mL) and stirred at ambienttemperature for 18 h. The solution was acidified with 1M HCl and theresulting solid was filtered and dried to give the title compound (0.945g, 80%).

Part D. Preparation of3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzaldehyde.

The product from Part C (0.945 g, 2.97 mmol) was taken up in thionylchloride (4.5 mL) and the mixture was heated at 80° C. for 40 min. Afterevaporation to dryness, the acid chloride was dissolved in dry THF (8mL) and cooled to −78° C. A 1 M solution of lithiumtri-tert-butoxyaluminum hydride in THF (3.0 mL, 3.0 mmol) was added dropwise. After 45 min the cold reaction was quenched with 1M HCl (5 mL),extracted into ethyl acetate, and purified by column chromatography onsilica gel, eluting with dichloromethane followed by 1%methanol/dichloromethane to give the title compound (0.635 g, 71%).

Part E. Preparation of(E)-1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)pyrimidine-2,4(1H,3H)-dione.

The product of Part D (0.634 g, 2.1 mmol) and diethyl4-nitrobenzylphosphonate (0.573 g, 2.1 mmol) were combined indichloromethane (25 mL) at ambient temperature. Potassium tert-butoxide(0.494 g, 4.4 mmol) was added portion wise and the resulting red/brownheterogeneous mixture was stirred for 1.5 h. This mixture was quenchedwith 1M HCl (15 mL), poured into water and extracted into ethyl acetate,and the crude product was purified by column chromatography on silicagel, eluting with 1% methanol/dichloromethane to give the title compound(0.735 g, 83%).

Part F. Preparation of(E)-1-(3-(4-aminostyryl)-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

The product from Part E (0.735 g, 1.74 mmol), ammonium chloride (0.14 g,2.62 mmol), and iron (0.487 g, 8.72 mmol) were combined in a solution ofethanol (10 mL), water (5 mL), and THF (10 mL) and heated at 75° C. for1 h. The mixture was filtered through diatomaceous earth, rinsing wellwith THF and concentrated to give the title compound.

Part G. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

The product from Part F (0.683 g, 1.75 mmol) and pyridine (0.564 mL,6.98 mmol) were combined in dichloromethane (15 mL) at ambienttemperature. Methane sulfonylchloride (0.163 mL, 2.1 mmol) was addeddrop wise and the solution was stirred for 18 h. The mixture was pouredinto 1M HCl and extracted into dichloromethane, concentrated, andpurified by column chromatography on silica gel, eluting with 1%, 2%methanol/dichloromethane. Trituration from dichloromethane provided asolid that was filtered and dried to give the title compound as acolorless powder (0.465 g, 57%). ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.38(s, 9H), 3.01 (s, 3H), 3.79 (s, 3H) 5.65 (d, J=7.72 Hz, 1H), 7.17-7.28(m, 5H), 7.58-7.70 (m, 3H), 7.75 (d, J=7.72 Hz, 1H), 9.86 (s, 1H), 11.42(s, 1H).

Example 13B Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.1

Part A. Preparation of N-(4-ethynylphenyl)methanesulfonamide

In a 2 L, 3-neck round-bottom flask equipped with an overhead stirrerwas added 4-ethynylaniline (30 g, 256 mmol) and pyridine (42.5 ml, 525mmol) in dichloromethane (512 ml) to give an orange solution. Themixture was cooled to 5° C. and methanesulfonyl chloride (19.96 ml, 256mmol) was added drop wise over 15 min. The reaction solution was stirredat 5° C. for 2 h and washed with 1M aqueous HCl (3×250 mL). Thedichloromethane layer was then washed sequentially with saturatedaqueous NaHCO₃, water, and saturated aqueous NaCl. The dichloromethanelayer was dried over sodium sulfate and treated simultaneously withdecolorizing charcoal for 30 min, the solution then filtered throughCelite and the filtrate was concentrated. The pink/orange solid wasdissolved in a minimal amount of hot ethyl acetate (50-75 mL) and slowlydiluted with hexanes (500-600 ml) to give orange crystals that werecollected by filtration and dried to provide the title compound (40.0 g,80%).

Part B. Preparation of (E)-4-(methylsulfonamido)styrylboronic acid.

(Reference: Org. Prep. Proc. Int., 2004, 36, 573-579) To a flask wasadded borane-methyl sulfide complex (8.03 mL, 85 mmol) followed bytetrahydrofuran (16 mL) and the mixture then cooled to 0° C.(1R)-(+)-alpha-pinene (26.2 mL, 169 mmol) was then added drop wise (over10 min) to the ice-cooled solution. The mixture was then stirred at 0°C. for 1 h followed by stirring 2 h at room temperature. The resultingthick white slurry was cooled to −40° C. in a dry ice/acetone bath,followed by the addition of the product from Part A (15.0 g, 77 mmol)dissolved in 60 mL of THF, drop wise over 30 min. After the addition wascomplete, the mixture was stirred for an additional hour at −35° C.,then 1 h at room temperature. The light yellow solution was then cooledto 0° C. and acetaldehyde (61.4 mL, 1088 mmol) added, then the mixturerefluxed at 50° C. for 18 h. The solvent was then removed under vacuumto provide an orange syrup, to which water (115 mL) was added and theheterogeneous mixture stirred for 3 h at room temperature. The lightyellow solid generated was collected and washed with water (250 mL) thendried in a vacuum oven overnight. The resultant material was thendissolved in boiling acetone (190 mL), which provided a homogenousyellow solution, followed by removal of the solution from heating andthe addition of hexanes (365 ml) over 5 min time. A white solid formedin the solution and the mixture was stirred until the solution cooled toroom temperature, then the white solid was collected and dried in avacuum oven for 1 hr to provide the title compound (12.1 g, 85%).

Part C. Preparation of 2-tert-butyl-4-nitrophenol.

To a vigorously stirred solution of 2-tert-butylphenol (10 g, 66.6 mmol)in heptane (67 ml) was added at a fast drip a solution of 70% nitricacid (4.25 ml, 66.6 mmol) diluted with water (4.25 ml). The resultingdark red/brown mixture was stirred vigorously for 2 h. The suspendedsolid was collected by filtration washed with hexane (300 mL), water(200 mL) and once again with hexane (200 mL) to give a cocoa coloredpowder that was dried to constant mass (4.65 g, 35.6%).

Part D. Preparation of 2-bromo-6-tert-butyl-4-nitrophenol.

A solution of the product from Part C (1.0 g, 5.12 mmol) in glacialacetic acid (10.25 mL) was treated portion wise with pyridinehydrobromide perbromide (1.80 g, 5.63 mmol) followed by stirring at roomtemperature for 2 h. Additional pyridinium hydrobromide perbromide (3.6g) was added in two portions and after another 3 h of stirring, thereaction was complete. The mixture was poured into ice water, and themixture treated with a small amount of sodium sulfite. The resultingsolid was filtered and dried under vacuum to give the title compound asa brown solid (1.40 g, 100%).

Part E. Preparation of 1-bromo-3-tert-butyl-2-methoxy-5-nitrobenzene.

A solution of the product from Part D (1.40 g, 5.11 mmol) in 10:1t-butylmethylether-methanol (25.5 mL) was treated with 2.0Mtrimethylsilyldiazomethane in ether (5.1 mL, 10.21 mmol), followed bystirring at room temperature for 18 h. The mixture was concentratedunder vacuum to afford a yellow oil, which was purified by silica gelcolumn chromatography eluting with EtOAc/hexanes to give the titlecompound as a yellow oil (1.36 g, 92%).

Part F. Preparation of tert-butyl3-bromo-5-tert-butyl-4-methoxyphenylcarbamate.

A solution of the product from Part E (960 mg, 3.33 mmol) in methanol(17 mL) was treated with 5% platinum on sulfided carbon (100 mg),followed by hydrogenation under balloon pressure for 3 h, and thenfiltered through celite and concentrated under vacuum to afford the3-bromo-5-tert-butyl-4-methoxyaniline as a yellow oil (860 mg, 3.33mmol, 100%). A solution of this material in THF (17 mL) was treated withdi-tert-butyl dicarbonate (800 mg, 3.66 mmol) followed by warming atreflux for 2 h. Concentration under vacuum afforded a beige solid, whichwas purified by silica gel column chromatography eluting withEtOAc/hexanes. Solid was triturated with hexanes, collected byfiltration, and dried under vacuum to give the title compound as anearly white solid (890 mg, 75%).

Part G. Preparation of(E)-N-(3-bromo-5-tert-butyl-4-methoxyphenylcarbamoyl)-3-methoxyacrylamide.

The product from Part F (2.0 g, 5.58 mmol) was dissolved indichloromethane (10 mL) and trifluoroacetic acid (5 mL) added. Thesolution was stirred at room temperature for 1 h followed byconcentration under vacuum and the addition of 10% aqueous sodiumbicarbonate (50 mL), followed by extraction with ethyl acetate (3×50mL). The combined organic extracts were dried and concentrated toprovide a residue that was dissolved in 10 mL of N,N-dimethylacetamideand cooled to −25° C. A 0.5 molar solution of E-3-methoxyacryloylisocyanate in benzene (20.3 mL, 11.16 mmol) was added drop wise and theresulting solution was stirred at ambient temperature for 4 h, and thenpoured into water. The product was extracted into dichloromethane,washed with brine, dried over sodium sulfate, filtered and evaporatedunder vacuum to give the title compound.

Part H. Preparation of1-(3-bromo-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

The product from Part G (2.15 g, 5.58 mmol) was dissolved in ethanol (10mL). To this solution was added a mixture of concentrated sulfuric acid(1 mL) and water (10 mL). The heterogeneous mixture was heated at 100°C. for 2 h. The ethanol was removed under vacuum, and then the aqueoussolution was extracted with dichloromethane and evaporated to dryness.This residue was purified by column chromatography on silica gel,eluting with 1% methanol/dichloromethane to yield the title compound(1.35 g, 69%).

Part I. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

The product from Part H (8.0 g, 22.65 mmol), the product from Part B(5.90 g, 24.46 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.738 g, 1.132 mmol), and potassium phosphate(9.62 g, 45.3 mmol) were dissolved in a mixture of tetrahydrofuran (128mL) and water (32 mL). Nitrogen gas was bubbled through the resultantmixture for 10 min followed by heating the solution at 50° C. for 5 h indarkness. The reaction was allowed to cool to room temperature followedby the addition of saturated aqueous ammonium chloride (50 mL), water(200 mL), and the solution extracted with dichloromethane (600 mL). Tothe organic extract was added magnesium sulfate, and3-mercaptopropyl-functionalized silica gel (20 g) and the resultantsolution stirred in darkness for 18 h. The solids were then removed byfiltration and the filtrate concentrated under vacuum and subjected tosilica gel column chromatography using a 99/1 to 99/2dichloromethane/methanol gradient to provide the title compound (7.4 g,70%). ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.38 (s, 9H), 3.01 (s, 3H), 3.79(s, 3H) 5.65 (d, J=7.72 Hz, 1H), 7.17-7.28 (m, 5H), 7.58-7.70 (m, 3H),7.75 (d, J=7.72 Hz, 1H), 9.86 (s, 1H), 11.42 (s, 1H).

Example 14 Preparation of(E)-N-(4-(3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.2

Part A. Preparation of methyl3-tert-butyl-5-(5-fluoro-6-methoxy-2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

The fluorination procedure was performed as described in Lal, G S, etal. J. Org Chem., 60:7340-7342 (1995). The product from Example 13A,Part B (0.42 g, 1.26 mmol) and Selectfluor™ (0.672 g, 1.9 mmol) werecombined in a mixture of acetonitrile (8 mL) and methanol (1 mL) andheated at 90° C. under N₂ for 5 h. The solution was diluted with water,extracted into ethyl acetate, washed with sodium bicarbonate solution,concentrated and purified by column chromatography on silica gel to givethe title compound (0.138 g, 29%).

Part B. Preparation of methyl3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

The product from Part A (0.134 g, 0.35 mmol) and triethylamine (1 mL)were combined in methanol (4 mL) and stirred at ambient temperature for18 h. The solution was quenched with 1M HCl, extracted intodichloromethane and concentrated to give the title compound (0.113 g,92%).

Part C. Preparation of3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzoicacid.

The product from Part B (0.113 g, 0.32 mmol) was treated as described inExample 13A, Part C to give the title compound (0.088 g, 81%).

Part D. Preparation of3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzaldehyde.

The product from Part C (0.088 g, 0.26 mmol) was treated as described inExample 13A, Part D to give the title compound (0.075 g, 90%).

Part E. Preparation of(E)-1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)-5-fluoropyrimidine-2,4(1H,3H)-dione.

The product of Part D (0.075 g, 0.23 mmol) was treated as described inExample 13A, Part E to give 0.077 g (75%).

Part F. Preparation of(E)-1-(3-(4-aminostyryl)-5-tert-butyl-4-methoxyphenyl)-5-fluoropyrimidine-2,4(1H,3H)-dione.

The product of Part E (0.077 g, 0.18 mmol) was treated as described inExample 13A, Part F to give the title compound (0.071 g, 94%).

Part G. Preparation of(E)-N-(4-(3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

The product of Part F (0.071 g, 0.17 mmol) was treated as described inExample 13A, Part G to give the title compound (0.048 g, 57%). ¹H NMR(300 MHz, DMSO-D6): δ ppm 1.38 (s, 9H), 3.01 (s, 3 H), 3.79 (s, 3H)7.19-7.27 (m, 5H), 7.62 (d, J=8.82 Hz, 2H), 7.66 (d, J=2.57 Hz, 1H),8.25 (d, J=6.99 Hz, 1H).

Example 15 Preparation of(E)-N-(4-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.52

Part A. Preparation of 2-bromo-4,6-diiodophenol.

A 1 L round-bottom flask was charged with 2-bromophenol (8.65 g, 50mmol) and methanol (100 ml) to give a colorless solution. Sodiumhydroxide (2.40 g, 60.0 mmol) was added and stirred until the hydroxidepellets had dissolved. The solution was cooled in an ice water bath andsodium iodide (5.6 g, 37.4 mmol) was added followed by drop-wiseaddition of sodium hypochlorite (17 mL, 27.5 mmol) to give a transparentbrown/red solution and gradual precipitation of a thick, white solid.The addition of sodium iodide and bleach was repeated 3 times to give anorange mixture that was stirred for 2 h, treated with a solution ofsodium thiosulfate in water (20 g in 100 mL), stirred for 15 min andtreated drop-wise with concentrated HCl to a constant pH of 1. Themixture was stirred for 15 min and filtered to collect a white solidthat was washed repeatedly with water and dried to constant mass (140.7g, 69%).

Part B. Preparation of 1-bromo-3,5-diiodo-2-methoxybenzene.

A 500 mL round-bottom flask was charged with the product from Part A(14.7 g, 34.6 mmol), iodomethane (2.70 ml, 43.3 mmol), and sodiumhydroxide (2.101 ml, 39.8 mmol) in acetone (96 ml) to give a tansolution. The mixture was stirred for 24 h and concentrated. The residuewas dissolved in ethyl acetate, washed with water and saturated sodiumchloride, dried over sodium sulfate, filtered and concentrated to give awhite solid. The solid was recrystallized from hot hexane to give awhite solid that was collected by filtration (12.3 g, 81%).

Part C. Preparation of1-(3-bromo-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

A 250 mL round-bottom flask was charged with the product from Part B(8.09 g, 18.44 mmol), pyrimidine-2,4(1H,3H)-dione (2.273 g, 20.28 mmol),N-(2-cyanophenyl)picolinamide (0.823 g, 3.69 mmol), copper (I) iodide(0.351 g, 1.844 mmol) and potassium phosphate (8.22 g, 38.7 mmol) inDMSO (70 ml). The mixture was sealed, sparged with nitrogen for 15 minand heated at 60° C. for 16 h. The mixture was partitioned with ethylacetate and water. The organic layer was washed with 1M HCl, water,brine, dried with sodium sulfate, and filtered. The filtrate was treatedwith 3-mercaptopropyl functionalized silica gel (Aldrich catalog#538086), filtered through celite and evaporated to give an off-whitesolid (3.92 g, 50%).

Part D. Preparation of(E)-N-(4-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

To a 100 ml round-bottom flask was added the product from Part C (846mg, 2.0 mmol), the product from Example 13B, Part B (482 mg, 2.000mmol), potassium phosphate (892 mg, 4.20 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (PA-Ph) (CAS97739-46-3) (17.54 mg, 0.060 mmol) andtris(dibenzylideneacetone)dipalladium(0) (18.31 mg, 0.020 mmol) in THF(12.0 ml) and water (4.0 ml). The flask was sealed and the mixture wassparged with nitrogen for 5 min and stirred at ambient temperature for72 h. The mixture was partitioned with ethyl acetate and 1M HCl. Theorganic layer was washed with saturated sodium bicarbonate, brine, driedwith sodium sulfate and filtered. The filtrate was treated with3-mercaptopropyl functionalized silica gel, filtered and evaporated. Theresidue was triturated with a minimal amount of methanol/CH₂Cl₂ to givethe title compound as a white solid (595 mg, 60%). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.03 (s, 3H) 3.82 (s, 3H) 5.69 (dd, J=7.72, 1.50 Hz, 1H)7.24 (d, J=8.46 Hz, 2H) 7.35 (m, 2H) 7.61 (d, J=8.46 Hz, 2H) 7.69 (d,J=2.21 Hz, 1H) 7.78 (d, J=8.09 Hz, 1H) 7.87 (d, J=2.21 Hz, 1H) 9.90 (s,1H) 11.50 (s, 1H). MS (ESI−) m/z 490, 492 (M−H)+.

Example 16 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophen-2-yl)styryl)phenyl)methanesulfonamideCompound IB-L1-1.48

To a 5 ml microwave tube was added the product from Example 15, Part D(40 mg, 0.081 mmol), thiophen-2-ylboronic acid (10.40 mg, 0.081 mmol),1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.65 mg,4.06 μmol) and potassium phosphate (34.5 mg, 0.162 mmol) in THF (3.0 ml)and water (1.0 ml). The vessel was sealed and the mixture was sparged bynitrogen for 5 min and heated at 50° C. for 3 h. The mixture waspartitioned with ethyl acetate and 1M HCl. The organic layer was washedwith saturated sodium bicarbonate, brine, dried with sodium sulfate andfiltered. The filtrate was treated with 3-mercaptopropyl functionalizedsilica gel, filtered through celite and evaporated. The residue waspurified by reverse phase chromatography to give the title compound as awhite solid (20 mg, 50%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.03 (s, 3H)3.70 (s, 3H) 5.70 (dd, J=7.72, 2.21 Hz, 1H) 7.18 (dd, J=5.43, 4.05 Hz,1H) 7.25 (d, J=8.82 Hz, 2H) 7.35 (s, 2H) 7.63 (d, J=8.82 Hz, 2H) 7.68(m, 2H) 7.77 (m, 2H) 7.83 (d, J=7.72 Hz, 1H) 9.89 (s, 1H) 11.49 (d,J=2.21 Hz, 1H). MS (ESI+) m/z 496 (M+H)+.

Example 17 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.46

The title compound was prepared according to the procedure of Example 16substituting furan-2-ylboronic acid for thiophen-2-ylboronic acid togive a white solid (22 mg, 56%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.03(s, 3H) 3.76 (s, 3H) 5.69 (d, J=7.72 Hz, 1H) 6.69 (dd, J=3.31, 1.84 Hz,1H) 7.08 (d, J=2.57 Hz, 1H) 7.25 (d, J=8.46 Hz, 2H) 7.36 (m, 2H) 7.63(d, J=8.82 Hz, 2H) 7.67 (d, J=2.57 Hz, 1H) 7.77 (d, J=2.57 Hz, 1H) 7.82(m, J=7.72 Hz, 2H) 9.88 (s, 1H) 11.48 (s, 1H). MS (ESI+) m/z 497(M+NH4)+.

Example 18 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(pyridin-4-yl)styryl)phenyl)methanesulfonamideCompound IB-L1-1.55

The title compound was prepared according to the procedure of Example 16substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine forthiophen-2-ylboronic acid to give a white solid (15 mg, 38%). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 3.03 (s, 3H) 3.49 (s, 3H) 5.72 (dd, J=7.72,2.21 Hz, 1H) 7.25 (d, J=8.46 Hz, 2H) 7.38 (d, J=4.41 Hz, 2H) 7.51 (d,J=2.57 Hz, 1H) 7.63 (d, J=8.82 Hz, 2 H) 7.80 (d, J=5.88 Hz, 2H) 7.85 (d,J=7.72 Hz, 1H) 7.97 (d, J=2.57 Hz, 1H) 8.77 (d, J=6.25 Hz, 2H) 9.90 (s,1H) 11.51 (d, J=2.21 Hz, 1H). MS (ESI+) m/z 491 (M+H)+.

Example 19 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(pyridin-3-yl)styryl)phenyl)methanesulfonamideCompound IB-L1-1.53

The title compound was prepared according to the procedure of Example 16substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine forthiophen-2-ylboronic acid to give a white solid (19 mg, 48%). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 3.02 (s, 3H) 3.45 (s, 3H) 5.71 (dd, J=8.09,2.21 Hz, 1H) 7.24 (d, J=8.46 Hz, 2H) 7.37 (d, J=2.94 Hz, 2H) 7.47 (d,J=2.57 Hz, 1H) 7.63 (m, 3H) 7.85 (d, J=7.72 Hz, 1H) 7.93 (d, J=2.57 Hz,1H) 8.15 (m, 1H) 8.68 (dd, J=4.80 Hz, 1.47 Hz, 1H) 8.86 (d, J=1.84 Hz,1H) 9.89 (s, 1H) 11.50 (d, J=2.21 Hz, 1H). MS (ESI+) m/z 491 (M+H)+.

Example 20 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophen-3-yl)styryl)phenyl)methanesulfonamideCompound IB-L1-1.47

The title compound was prepared according to the procedure of Example 16substituting thiophen-3-ylboronic acid for thiophen-2-ylboronic acid togive a white solid (19 mg, 38%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.02(s, 3H) 3.55 (s, 3H) 5.69 (d, J=8.09 Hz, 1H) 7.24 (d, J=8.46 Hz, 2H)7.36 (s, 2H) 7.55 (m, 2H) 7.61 (d, J=8.46 Hz, 2H) 7.67 (dd, J=5.15, 2.94Hz, 1H) 7.78 (d, J=2.57 Hz, 1 H) 7.83 (d, J=7.72 Hz, 1H) 7.93 (dd,J=2.57, 0.96 Hz, 1H) 9.88 (s, 1H) 11.48 (s, 1H). MS (ESI−) m/z 494(M−H)+.

Example 21 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.50

The title compound was prepared according to the procedure of Example 16substituting furan-3-ylboronic acid for thiophen-2-ylboronic acid togive a white solid (14 mg, 29%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.02(s, 3H) 3.69 (s, 3H) 5.69 (d, J=8.09 Hz, 1H) 7.05 (dd, J=2.57, 0.90 Hz,1 H) 7.24 (d, J=8.82 Hz, 2H) 7.34 (s, 2H) 7.61 (m, 3H) 7.74 (d, J=2.57Hz, 1H) 7.80 (m, 2H) 8.25 (s, 1 H) 9.88 (s, 1H) 11.49 (s, 1H). MS (ESI−)m/z 478 (M−H)+.

Example 22 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L-1.45

Part A. Preparation of 2-(2-hydroxy-3,5-diiodophenyl)acetic acid.

To a 250 mL round-bottom flask was added 2-(2-hydroxyphenyl)acetic acid(Aldrich, 3.04 g, 20 mmol) in acetonitrile (50 ml) to give a colorlesssolution. N-iodosuccimide (9.00 g, 40.0 mmol) was added portionwise over15 min to give a red/brown transparent solution that was stirred for 16h. The mixture was concentrated and the resulting solid was trituratedin 75 mL of water and filtered to collect an orange solid that was driedunder vacuum. The crude solid was recrystallized from toluene to give alight orange powder (6.0 g, 74%).

Part B. Preparation of methyl 2-(3,5-diiodo-2-methoxyphenyl)acetate.

To a 250 mL round-bottom flask was added the product from Part A (6 g,14.85 mmol), potassium carbonate (6.16 g, 44.6 mmol), and dimethylsulfate (4.12 g, 32.7 mmol) in acetone (49.5 ml) to give a brownsuspension. The suspension was heated at reflux for 16 h, cooled,concentrated and the residue was partitioned between EtOAc and water.The EtOAc layer was washed with brine, dried (Na₂SO₄) and concentratedto a brown oil that was chromatographed on a 40 g silica cartridgeeluting with 3:1 hexane/EtOAc to give a yellow oil (6.0 g, 94%).

Part C. Preparation of methyl2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropanoate.

To a 100 mL round-bottom flask under nitrogen was added the product fromPart B (1.728 g, 4 mmol) in anhydrous THF (20 ml) and HMPA (2 ml) togive a colorless solution. Methyl iodide (1.251 ml, 20.00 mmol) wasadded and the solution was cooled to −40° C. Potassium t-butoxide (12.00ml, 12.00 mmol) was added drop-wise and the mixture was stirred at −40to −20° C. for 30 min and quenched with 1M HCl to a pH of 1. The mixturewas extracted 3×40 ml with EtOAc. The extracts were combined, washedwith brine, dried (Na₂SO₄) and concentrated. The crude product was flashchromatographed on a 40 g ISCO silica cartridge eluting with 9:1hexane/EtOAc to give the bis-methylated product as a yellow oil (1.63 g,89%).

Part D. Preparation of 2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropanoicacid.

A suspension of the product from Part C (2.63 g, 5.72 mmol) in MeOH (40ml) and THF (40 ml) was treated with 4.0M sodium hydroxide (28 ml, 112mmol) and heated at 80° C. for 48 h. The organic solvent was evaporatedand the remaining aqueous solution was acidified with 1M HCl producing asolid that was collected by filtration, washed with water and dried togive the desired carboxylic acid (2.46 g, 96%).

Part E. Preparation of2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropan-1-ol.

A solution of the product from Part D (1.00 g, 2.242 mmol) in THF (40ml) was treated drop-wise with borane THF complex 1.0M (20 ml, 20 mmol)and then heated at 50° C. for 24 h. The mixture was treated withmethanol (20 mL), refluxed for 30 min and concentrated. The resultingresidue was washed with water, brine, dried with sodium sulfate,filtered and evaporated. The residue was chromatographed on silica geleluting with hexane/EtOAc (4:1) to give the desired product (810 mg,84%).

Part F. Preparation oftert-butyl(2-(3,5-diiodo-2-methoxyphenyl)-2-methylpropoxy)dimethylsilane.

A solution of the product from Part E (432 mg, 1.000 mmol) in DMF (5 ml)was treated with tert-butyldimethylchlorosilane (301 mg, 2.000 mmol),and imidazole (204 mg, 3.00 mmol) and stirred for 2 h. The mixture waspartitioned between 1M HCl and ethyl acetate. The organic layer waswashed with saturated sodium bicarbonate, brine, dried with sodiumsulfate, filtered and evaporated. The residue was chromatographed onsilica gel eluting with hexane/EtOAc (9:1) to give the desired product(522 mg, 96%).

Part G. Preparation of1-(3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

To a 50 mL round-bottom flask was added the product from Part F (520 mg,0.952 mmol), pyrimidine-2,4(1H,3H)-dione (117 mg, 1.047 mmol),N-(2-cyanophenyl)picolinamide (42.5 mg, 0.190 mmol), copper(I) iodide(18.13 mg, 0.095 mmol) and potassium phosphate (424 mg, 1.999 mmol) inDMSO (5 ml). The vessel was sealed, sparged with nitrogen and thenheated at 60° C. for 24 h. The mixture was partitioned between 1M HCland ethyl acetate. The organic layer was washed with saturated sodiumbicarbonate, brine, dried with sodium sulfate, and filtered. Thefiltrate was treated with 3-mercaptopropyl functionalized silica gel,filtered and evaporated. The residue was chromatographed on silica geleluting with hexane/EtOAc (3:2) to give the product as a solid (285 mg,65%).

Part H. Preparation of(E)-N-(4-(3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

To a 5 ml microwave tube was added the product from Part G (53 mg, 0.1mmol), the product from Example 13B, Part B (24 mg, 0.1 mmol), potassiumphosphate (44.0 mg, 0.2 mmol), PA-Ph (CAS 97739-46-3) (0.87 mg, 3.0μmol) and tris(dibenzylideneacetone)palladium(0) (0.9 mg, 1 μmol) in THF(3.0 ml) and water (1.0 ml). The vessel was sealed and the mixture wassparged with nitrogen for 5 min and then heated at 50° C. for 2 h. Themixture was partitioned between 1M HCl and ethyl acetate. The organiclayer was washed with saturated sodium bicarbonate, brine, dried withsodium sulfate and filtered. The filtrate was treated with3-mercaptopropyl functionalized silica gel, filtered and evaporated. Theresidue was chromatographed on silica gel eluting with hexane/EtOAc(1:1) to give a solid (50 mg, 83%)

Part I. Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxystyryl)phenyl)methanesulfonamide.

A solution of the product from Part H (120 mg, 0.20 mmol) in THF (5.0ml) was treated with 1 M TBAF (0.800 ml, 0.800 mmol) in THF and stirredfor 16 h. The mixture was partitioned with water and ethyl acetate. Theorganic layer was washed (3× brine), dried with sodium sulfate, filteredand evaporated. The residue was chromatographed on silica gel elutingwith 4% methanol in CH₂Cl₂ to give a solid (85 mg, 88%). ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.30 (s, 6H) 3.01 (s, 3H) 3.62 (d, J=5.52 Hz, 2H)3.77 (s, 3H) 4.67 (t, J=5.33 Hz, 1H) 5.66 (d, J=8.09 Hz, 1H) 7.21 (m,5H) 7.62 (m, 3H) 7.72 (d, J=8.09 Hz, 1H) 9.85 (s, 1H) 11.42 (s, 1H). MS(ESI+) m/z 503 (M+NH4)+.

Example 23 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodo-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.51

Part A. Preparation of 1,3,5-triiodo-2-methoxybenzene.

In a 250 mL pressure vessel was added 2,4,6-triiodophenol (5 g, 10.60mmol) in MTBE (60 ml) to give a yellow solution. The solution was cooledin an ice bath and 2.0M trimethylsilyldiazomethane (7.95 ml, 15.90 mmol)was added at a fast drip followed by dropwise addition of methanol (6mL) resulting in calm bubbling. The vessel was sealed and stirred atroom temperature for 4 h. The reaction solution was partitioned betweenEtOAc and water and the organic layer was washed with 1M HCl, saturatedNaHCO₃, and saturated NaCl. The EtOAc was dried (MgSO₄), filtered andconcentrated to give a tan solid that was used without purification (4.8g, 94%).

Part B. Preparation of1-(3,5-diiodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

To a 100 mL round-bottom flask under N₂ was added the product from PartA (3.5 g, 7.2 mmol), 1H-pyrimidine-2,4-dione (0.97 g, 8.64 mmol), andpotassium phosphate tribasic (3.2 g, 15.0 mmol) in DMSO (50 ml) to givea colorless suspension. N-(2-cyanophenyl)picolinamide (320 mg, 1.44mmol) was added and the mix was sparged with N₂ for 5 min. Copper(I)iodide (137 mg, 0.72 mmol) was added and the mix was sparged once againfor 10 min, placed under N₂ and heated at 60° C. for 18 h. The mixturewas cooled and partitioned between EtOAc and water adjusting the pH to 1with HCl. The aqueous layer was extracted 2× with EtOAc. The organicswere combined, washed with water, saturated NaHCO₃, and saturated NaCl,dried (Na₂SO₄), treated with 3-mercaptopropyl functionalized silica,filtered and concentrated. The resulting solid was triturated in 2:1hexane/EtOAc to give an off white powder (2.2 g, 62%).

Part C. Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodo-2-methoxystyryl)phenyl)methanesulfonamide.

In a 5 ml microwave tube was mixed the product from Part B (141 mg, 0.30mmol), the product from Example 13B, Part B (72.3 mg, 0.300 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride CH₂Cl₂complex (12.25 mg, 0.015 mmol) and potassium phosphate (70.0 mg, 0.330mmol) in THF (3.0 ml) and water (1.0 ml). The mixture was sparged withnitrogen for 5 min and heated at 50° C. for 2 h. The mixture waspartitioned with ethyl acetate and 1M HCl. The organic layer was washedwith saturated sodium bicarbonate, brine, dried with sodium sulfate andfiltered. The filtrate was treated with 3-mercaptopropyl functionalizedsilica gel, filtered and evaporated. The residue was chromatographed onsilica eluting with 5% methanol in CH₂Cl₂ to give a solid (47 mg, 29%).¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.02 (s, 3H) 3.77 (s, 3H) 5.67 (d,J=7.72 Hz, 1H) 7.28 (m, 4H) 7.60 (d, J=8.82 Hz, 2H) 7.76 (d, J=8.09 Hz,1H) 7.81 (d, J=2.57 Hz, 1H) 7.86 (d, J=2.21 Hz, 1H) 9.90 (s, 1H) 11.48(s, 1H). MS (ESI−) m/z 538 (M−H)+.

Example 24 Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulfonyl)styryl)phenyl)methanesulfonamideCompound IB-L1-1.49

Part A. Preparation of 4-nitrobenzene-2-diazo-1-oxide.

To a 250 mL round-bottom flask was added 2-amino-4-nitrophenol (6.165 g,40.0 mmol) in 48% tetrafluoroboric acid (15 ml). Sodium nitrite (2.76 g,40.0 mmol) in water (6 ml) was added dropwise at 0° C. and the mixturewas stirred at room temperature for 30 min. The solid was collected byfiltration, washed with tetrafluoroboric acid and water. The solid wassuspended in acetone (50 ml), filtered and dried to give a solid (3.31g, 50%).

Part B. Preparation of 2-(methylthio)-4-nitrophenol.

To a 1 L beaker was added the product from Part A (2.70 g, 16.35 mmol)in ice water (250 g) to give a brown suspension. Copper (0.520 g, 8.18mmol) was added, followed by addition of sodium thiomethoxide (2.292 g,32.7 mmol) in water (50 ml) slowly. The mixture was stirred at roomtemperature for 24 h. The mixture was filtered and the filtrate wasacidified with 1M HCl producing a solid that was collected by filtrationand dried (2.53 g, 84%).

Part C. Preparation of 2-(methylsulfonyl)-4-nitrophenol.

To a 250 mL round-bottom flask was added the product from Part B (1.111g, 6.00 mmol) in MeOH (20 ml) to give a brown suspension. Oxone (7.746g, 12.60 mmol) in water (20 ml) was added slowly at 0° C. The mixturewas warmed to room temperature, stirred for 1 h and partitioned withethyl acetate and 1M HCl. The organic layer was washed with brine, driedwith sodium sulfate, filtered and evaporated. The residue waschromatographed on silica gel eluting with 1% to 5% methanol in CH₂Cl₂to give a solid (0.472 g, 36%).

Part D. Preparation of 2-iodo-6-(methylsulfonyl)-4-nitrophenol.

To a 50 mL round-bottom flask was added the product from Part C (470 mg,2.164 mmol) in MeOH (10 ml) and water (2.5 ml). Iodine monochloride(0.130 ml, 2.60 mmol) in CH₂Cl₂ (2.0 mL) was added drop-wise and themixture was stirred at room temperature, poured into water (200 mL) andstirred for 10 min. The resulting solid was collected by filtration anddried (636 mg, 86%).

Part E. Preparation of1-iodo-2-methoxy-3-(methylsulfonyl)-5-nitrobenzene.

To a 50 mL pressure vessel was added the product from Part D (630 mg,1.836 mmol) in MTBE (6 ml) to give a yellow solution. The mixture wascooled in an ice bath and 2M trimethylsilyldiazomethane (1.377 ml, 2.75mmol) was added at a fast drip followed by drop-wise addition of MeOH(0.4 ml) resulting in calm bubbling. The vessel was sealed and stirredat room temperature for 1 h. The mixture was partitioned with ethylacetate and 1M HCl. The organic layer was washed with saturated sodiumbicarbonate, brine, dried with sodium sulfate, filtered and evaporatedto give an off-white solid (655 mg, 100%).

Part F. Preparation of 3-iodo-4-methoxy-5-(methylsulfonyl)aniline.

To a 250 mL round-bottom flask was added the product from Part E (0.650g, 1.820 mmol), ammonium chloride (0.146 g, 2.73 mmol), and iron (0.508g, 9.10 mmol) in THF/MeOH/water (50 ml, 2/2/1). The mixture was refluxedfor 2 h, cooled and filtered. The filtrate was evaporated and theresidue was partitioned with ethyl acetate and water. The organic layerwas washed with brine, dried with sodium sulfate, filtered andevaporated to give a solid (590 mg, 99%).

Part G. Preparation of(E)-N-(3-iodo-4-methoxy-5-(methylsulfonyl)phenylcarbamoyl)-3-methoxyacrylamide.

To a 100 mL round-bottom flask was added the product from Part F (500mg, 1.528 mmol) in DMF (15.0 ml). The solution was cooled under nitrogento −20° C. and (E)-3-methoxyacryloyl isocyanate (15.28 ml, 6.11 mmol;prepared as described by Santana, L.; et al. J. Heterocyclic Chem. 1999,36, 293-295) was added dropwise. The mixture was stirred at thistemperature for 15 min, then warmed to room temperature and stirred for45 min. The mixture was diluted with ethyl acetate and washed by water(3×50 ml), brine (3×50 ml), dried with sodium sulfate, filtered andevaporated. The residue was triturated with ethyl acetate/hexane to givea solid (425 mg, 61%).

Part H. Preparation of1-(3-iodo-4-methoxy-5-(methylsulfonyl)phenyl)pyrimidine-2,4(1H,3H)-dione.

To a 100 mL round-bottom flask was added the product from Part G (420mg, 0.925 mmol) in ethanol (10 ml) to give a suspension. Concentratedsulfuric acid (1 mL, 18.76 mmol) in water (10 ml) was added and themixture was heated at 110° C. for 2 h. The reaction mix was cooled,diluted with water (50 ml) and stirred for 10 min. The solid materialwas collected by filtration, washed with water and dried to give a whitesolid (325 mg, 83%).

Part I. Preparation of(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulfonyl)styryl)phenyl)methanesulfonamide.

In a 5 ml microwave tube was added the product from Part H (63.3 mg,0.15 mmol), the product from Example 13B, Part B (36.2 mg, 0.150 mmol),potassium phosphate (66.9 mg, 0.315 mmol), PA-Ph (CAS 97739-46-3) (1.315mg, 4.50 μmol) and tris(dibenzylideneacetone)dipalladium(0) (1.374 mg,1.500 μmol) in THF (3.0 ml) and water (1.0 ml). The vessel was sealedand the mixture was sparged with nitrogen for 5 min and heated at 50° C.for 2 h. The mixture was partitioned with ethyl acetate and 1M HCl. Theorganic layer was washed with saturated sodium bicarbonate, brine, driedwith sodium sulfate and filtered. The filtrate was treated with3-mercaprpropyl functionalized silica gel, filtered and evaporated. Theresidue was triturated with methanol/CH₂Cl₂ to give a solid (62 mg,84%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.03 (s, 3H) 3.37 (s, 3H) 3.94 (s,3H) 5.72 (d, J=7.72 Hz, 1H) 7.26 (m, 3H) 7.45 (m, 1H) 7.65 (d, J=8.46Hz, 2H) 7.77 (d, J=2.57 Hz, 1H) 7.81 (d, J=8.09 Hz, 1H) 8.21 (d, J=2.57Hz, 1H) 9.93 (s, 1H) 11.52 (s, 1H). MS (ESI+) m/z 509 (M+NH4)+.

Example 25 Preparation of (E)-methyl2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-5-(methylsulfonamido)benzoateCompound IB-L1-1.7

Part A. Preparation of methyl2-((diethoxyphosphoryl)methyl)-5-nitrobenzoate.

To a solution of methyl 2-methyl-5-nitrobenzoate (0.40 g, 2.05 mmol) inCCl₄ (20 ml) was added N-bromosuccinimide (365 mg, 2.05 mmol) and2,2′-azobisisobutyronitrile (34 mg, 0.21 mmol). The resulting mixturewas stirred at reflux for 18 h, cooled to room temperature andpartitioned between EtOAc (50 ml) and H₂O (50 ml). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by column chromatography on silica gel using 1:3EtOAc:hexanes as the eluent to give the bromide as an oil (345 mg, 61%).The oil was placed in triethylphosphite (5 ml) and heated with stirringat 120° C. for 3 h. The mixture was allowed to cool to room temperature,and the crude product was purified by column chromatography on silicagel using 5% MeOH in CH₂Cl₂ as the eluent. The title compound wasobtained as an oil (313 mg, 75%).

Part B. Preparation of (E)-methyl2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-5-nitrobenzoate.

To a solution of the product from Part A (360 mg, 1.09 mmol) and theproduct from Example 13A, Part D (329 mg, 1.09 mmol) in anhydrous CH₂Cl₂(10 ml) was added potassium tert-butoxide (305 mg, 2.72 mmol). Theresulting dark red solution was stirred at room temperature for 1 h, andthen poured into 1 N aq. HCl (10 ml). The resulting mixture wasextracted with CH₂Cl₂ (10 ml), dried over Na₂SO₄, filtered andconcentrated in vacuo to give a solid. A solution of the solid inthionyl chloride (2.3 ml) was heated at 85° C. for 30 min, and thethionyl chloride was removed in vacuo. The residue was stirred in a 2:1mixture of CH₂Cl₂ and MeOH (3 ml) for 30 min, and evaporated to drynessin vacuo. The crude product was purified by column chromatography onsilica gel using 3% MeOH in CH₂Cl₂ as the eluent to give the titlecompound (350 mg, 69%).

Part C. Preparation of (E)-methyl2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-5-(methylsulfonamido)benzoate.

To a solution of the product from Part B (465 mg, 0.97 mmol) in a 2:2:1mixture of THF:MeOH:H₂O (10 ml) was added iron powder (271 mg, 4.85mmol), and ammonium chloride (78 mg, 1.46 mmol). The mixture was heatedat 80° C. for 45 min, filtered through celite, and concentrated todryness in vacuo. The residue was combined with methanesulfonyl chloride(0.16 ml, 2.0 mmol) and triethylamine (0.392 ml, 4.85 mmol) in anhydrousCH₂Cl₂ (10 ml) and the resulting mixture was stirred at room temperaturefor 3 h. The mixture was partitioned between 1 N HCl (20 ml) and CH₂Cl₂(20 ml), and the organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel using 3% MeOH in CH₂Cl₂ as the eluent togive the title compound (270 mg, 53%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.42(s, 1H) 10.07 (s, 1H) 7.90 (d, J=8.82 Hz, 1H) 7.66-7.79 (m, 3H) 7.52 (d,J=2.57 Hz, 1H) 7.44 (dd, J=8.64, 2.39 Hz, 1H) 7.14-7.26 (m, 2H) 5.65(dd, J=7.72, 1.84 Hz, 1H) 3.86 (s, 3H) 3.79 (s, 3H) 3.04 (s, 3H) 1.38(s, 9H).

Example 26 Preparation of(E)-2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-5-(methylsulfonamido)benzoicAcid Compound IB-L1-1.4

A solution of the product from Example 25 (55 mg, 0.104 mmol) in THF (1ml) and 1N aq. NaOH (1 ml) was stirred in the dark at room temperaturefor 1.5 h. 1N aqueous HCl was added until pH 3, and the resultingmixture was extracted with EtOAc (2×2 ml). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to give the titlecompound (53 mg, 99%). ¹H NMR (300 MHz, DMSO-d₆) δ 13.22 (br s, 1H)11.40 (d, J=2.21 Hz, 1H) 10.02 (s, 1H) 7.72-7.91 (m, 3H) 7.68 (d, J=2.57Hz, 1H) 7.49 (d, J=2.57 Hz, 1H) 7.42 (dd, J=8.64, 2.39 Hz, 1H) 7.21 (d,J=2.57 Hz, 1H) 7.16 (d, J=16.18 Hz, 1H) 5.64 (dd, J=7.72, 2.21 Hz, 1H)3.79 (s, 3H) 3.04 (s, 3H) 1.38 (s, 9H).

Example 27 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-(morpholine-4-carbonyl)phenyl)methanesulfonamideCompound IB-L1-1.23

Part A. Preparation of(E)-2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-5-(methylsulfonamido)benzoylchloride.

A solution of the product from Example 26 (257 mg, 0.50 mmol) in thionylchloride (1.5 ml) was heated at 85° C. for 40 min and then concentratedand dried in vacuo to give the title compound as a solid (0.27 g).

Part B. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-(morpholine-4-carbonyl)phenyl)methanesulfonamide.

To a solution of the product from Part A (24 mg, 0.045 mmol) inanhydrous CH₂Cl₂ (1 ml) was added morpholine (0.02 ml, 0.226 mmol). Themixture was stirred at room temperature for 2 h, and then partitionedbetween 1 N aq. HCl (5 ml) and EtOAc (2×5 ml). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by column chromatography on silica gel using4% MeOH in CH₂Cl₂ as the eluent to give the title compound (19 mg, 71%).¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.41 (d, J=1.84 Hz, 1H) 10.04 (s, 1H)7.85 (d, J=8.46 Hz, 1H) 7.75 (d, J=8.09 Hz, 1H) 7.52 (d, J=2.57 Hz, 1H)6.99-7.34 (m, 5H) 5.65 (dd, J=7.72, 1.84 Hz, 1H) 3.76 (s, 3H) 3.56-3.71(m, 4H) 3.40-3.51 (m, 2H) 3.11-3.22 (m, 2H) 3.06 (s, 3H) 1.38 (s, 9H).

Example 28 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-(hydroxymethyl)phenyl)methanesulfonamideCompound IB-L1-1.10

To a solution of the product from Example 27, Part A (375 mg, 0.705mmol) in anhydrous THF (5 ml) at 0° C. under N₂ gas was added a 1.0 Msolution of lithium tert-butoxyaluminiumhydride (1.8 ml, 1.8 mmol)dropwise. The resulting mixture was stirred at 0° C. for 30 min, andthen allowed to warm to room temperature and was stirred for 1 h. Themixture was partitioned between 1 N aq. HCl (10 ml) and EtOAc (2×10 ml).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel using 3% MeOH in CH₂Cl₂ as the eluent togive the title compound (220 mg, 63%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.41 (s, 1H) 9.82 (s, 1H) 7.73 (t, J=8.27 Hz, 2H) 7.66 (d, J=2.57 Hz,1H) 7.31-7.39 (m, 2H) 7.20 (d, J=2.57 Hz, 1H) 7.12-7.19 (m, 2H) 5.65 (d,J=8.09 Hz, 1H) 5.28 (t, J=5.52 Hz, 1H) 4.65 (d, J=5.52 Hz, 2H) 3.79 (s,3H) 3.00 (s, 3H) 1.38 (s, 9H).

Example 29 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-(methoxymethyl)phenyl)methanesulfonamideCompound IB-L1-1.13

To a solution of the product from Example 28 (32 mg, 0.064 mmol) inanhydrous CH₂Cl₂ (1 ml) was added thionyl chloride (23 μL, 0.32 mmol),and the resulting mixture was stirred at room temperature for 30 min.The mixture was partitioned between saturated aq. NaHCO₃ (5 ml) andCH₂Cl₂ (5 ml) and the organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in MeOH (1 ml), and a solutionof 25% NaOMe in MeOH (58 μL, 0.254 mmol) was added. The resultingmixture was stirred at 50° C. for 2 h. The mixture was partitionedbetween 1 N aq. HCl (10 ml) and EtOAc (2×10 ml). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by column chromatography on silica gel using3% MeOH in CH₂Cl₂ as the eluent to give the title compound (15 mg, 46%).¹H NMR (300 MHz, DMSO-d₆) δ 11.43 (s, 1H) 9.86 (s, 1H) 7.62-7.87 (m, 3H)7.12-7.39 (m, 5H) 5.66 (d, J=7.72 Hz, 1H) 4.58 (s, 2H) 3.78 (s, 3H) 3.35(s, 3H) 3.00 (s, 3H) 1.38 (s, 9H).

Example 30 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-((isopentylamino)methyl)phenyl)methanesulfonamideCompound IB-L1-1.31

Part A. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-formylphenyl)methanesulfonamide.

To a solution of the product from Example 28 (0.60 g, 1.20 mmol) inanhydrous DMA (15 ml) was added 2-iodoxybenzoic acid (336 mg, 1.20mmol). The mixture was stirred at room temperature for 1 h, and thenpartitioned between EtOAc (20 ml) and H₂O (2×20 ml). The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel using 2%MeOH in CH₂Cl₂ as the eluent to give the title compound as a colorlesssolid (395 mg, 66%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.43 (d, J=2.21Hz, 1H) 10.45 (s, 1H) 10.15 (s, 1H) 8.06 (d, J=16.18 Hz, 1H) 7.97 (d,J=8.82 Hz, 1H) 7.73-7.78 (m, 2H) 7.69 (d, J=2.57 Hz, 1H) 7.51 (dd,J=8.64, 2.39 Hz, 1H) 7.30 (d, J=16.18 Hz, 1H) 7.26 (d, J=2.57 Hz, 1H)5.66 (dd, J=7.72, 2.21 Hz, 1H) 3.81 (s, 3H) 3.07 (s, 3H) 1.39 (s, 9H).

Part B. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-((isopentylamino)methyl)phenyl)methanesulfonamide.

To a solution of the product from Part A (50 mg, 0.10 mmol) and3-methylbutan-1-amine (12 μL, 0.10 mmol) in anhydrous THF (3 ml) wasadded sodium triacetoxyborohydride (32 mg, 0.15 mmol) and AcOH (9 μL,0.15 mmol). The resulting mixture was stirred at room temperature for 4h, and then partitioned between H₂O (10 ml) and EtOAc (2×10 ml). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel using 3% MeOH in CH₂Cl₂ as the eluent togive the title compound (37 mg, 65%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.45(d, J=1.84 Hz, 1H) 10.04 (s, 1H) 8.80-8.87 (m, 1H) 7.88 (d, J=8.46 Hz,1H) 7.71-7.77 (m, 2H) 7.41-7.48 (m, 1H) 7.37 (d, J=2.21 Hz, 1H)7.21-7.29 (m, 3H) 5.67 (dd, J=7.91, 2.02 Hz, 1H) 4.30-4.38 (m, 2H) 3.80(s, 3H) 3.10 (s, 3H) 2.95-3.04 (m, 2H) 1.49-1.67 (m, 3H) 1.38 (s, 9H)0.86 (d, J=6.25 Hz, 6H).

Example 31 Preparation ofN-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-((E)-(methoxyimino)methyl)phenyl)methanesulfonamideCompound IB-L1-1.19

To a solution of the product from Example 30, Part A (35 mg, 0.070 mmol)in EtOH (2 ml) was added O-methoxylamine hydrochloride (29 mg, 0.35mmol) and sodium bicarbonate (30 mg, 0.35 mmol). The resulting mixturewas stirred at 70° C. for 2 h. To the mixture was added 1 N aq. HCl (1ml) to give a colorless precipitate that was filtered and dried to givethe title compound as a colorless solid (24 mg, 64%). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.43 (d, J=2.21 Hz, 1H) 9.94 (s, 1H) 8.74 (s, 1H)7.79-7.85 (m, 2H) 7.76 (d, J=7.72 Hz, 1H) 7.57-7.65 (m, 2H) 7.32 (dd,J=8.64, 2.39 Hz, 1H) 7.23 (d, J=2.57 Hz, 1H) 7.18 (d, J=116.18 Hz, 1H)5.66 (dd, J=7.72, 2.21 Hz, 1H) 3.93 (s, 3H) 3.79 (s, 3H) 3.03 (s, 3H)1.38 (s, 9H).

Example 32 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-(oxazol-2-yl)phenyl)methanesulfonamideCompound IB-L1-1.26

To a solution of the product from Example 27, Part A (80 mg, 0.15 mmol)in tetramethylene sulfone (1.5 ml) was added 1H-1,2,3-triazole (10 μL,0.17 mmol) and potassium carbonate (73 mg, 0.53 mmol). The mixture washeated for 35 min at 130° C. in a microwave reactor. After cooling toroom temperature, the mixture was partitioned between 1 N aqueous HCl(10 ml) and EtOAc (2×10 ml). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by column chromatography on silica gel using 3% MeOH in CH₂Cl₂as the eluent to give the title compound (37 mg, 46%). ¹H NMR (300 MHz,DMSO-d₆) 311.41 (d, J=1.84 Hz, 1H) 10.10 (s, 1H) 8.29 (d, J=1.10 Hz, 1H)8.05 (d, J=16.18 Hz, 1H) 7.95 (d, J=8.82 Hz, 1H) 7.82 (d, J=2.21 Hz, 1H)7.74 (d, J=8.09 Hz, 1H) 7.51 (d, J=2.57 Hz, 1H) 7.46 (d, J=0.74 Hz, 1H)7.39 (dd, J=8.64, 2.39 Hz, 1H) 7.20-7.30 (m, 2H) 5.65 (dd, J=7.91, 2.02Hz, 1H) 3.80 (s, 3H) 3.07 (s, 3H) 1.38 (s, 9H).

Example 33 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-3-(1H-imidazol-2-yl)phenyl)methanesulfonamideCompound IB-L1-1.16

To a solution of the product from Example 30, Part A (50 mg, 0.10 mmol)in EtOH (2 ml) was added glyoxal (57 uL, 0.50 mmol) and concentratedaqueous NH₄OH (70 uL, 0.50 mmol). The resulting mixture was stirred atroom temperature for 16 h. To the mixture was added 1 N aq. HCl untilpH=7, and the mixture was partitioned between H₂O (10 ml) and EtOAc(2×10 ml). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by columnchromatography on silica gel using 5% MeOH in CH₂Cl₂ as the eluent togive the title compound (27 mg, 50%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.39(s, 1H) 11.40 (d, J=1.84 Hz, 1H) 9.98 (s, 1H) 7.89 (d, J=8.82 Hz, 1H)7.66-7.76 (m, 2H) 7.38 (t, J=2.21 Hz, 2H) 7.23-7.31 (m, 2H) 7.06-7.21(m, 3H) 5.63 (dd, J=8.09, 1.84 Hz, 1H) 3.78 (s, 3H) 3.07 (s, 3H) 1.37(s, 9H).

Example 34 Preparation of (E)-tert-butyl2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-5-(methylsulfonamido)phenylcarbamateCompound IB-L1-1.32

To a solution of the product from Example 26 (75 mg, 0.146 mmol) intert-butanol (4 ml) was added diphenylphosphoryl azide (47 μL 0.219mmol) and triethylamine (31 μL, 0.219 mmol). The resulting mixture wasstirred at 80° C. for 18 h. The cooled mixture was partitioned betweenH₂O (10 ml) and EtOAc (2×10 ml). The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by column chromatography on silica gel using 3% MeOH in CH₂Cl₂as the eluent to give the title compound (16 mg, 19%). ¹H NMR (300 MHz,DMSO-d₆) δ 11.45 (d, J=1.84 Hz, 1H) 9.86 (s, 1H) 9.03 (s, 1H) 7.75 (d,J=7.72 Hz, 2H) 7.55 (d, J=2.57 Hz, 1H) 7.10-7.33 (m, 4H) 7.04 (dd,J=8.64, 2.39 Hz, 1H) 5.66 (dd, J=7.91, 2.02 Hz, 1H) 3.78 (s, 3H) 3.02(s, 3H) 1.45 (s, 9H) 1.38 (s, 9H).

Example 35 Preparation of(E)-N-(3-amino-4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.28

The procedure described for the preparation of Example 34 provided thetitle compound, which was purified by column chromatography on silicagel using 5% methanol in CH₂Cl₂ as the eluent (6 mg, 9%). ¹H NMR (300MHz, DMSO-d₆) δ 11.44 (d, J=2.21 Hz, 1H) 9.55 (s, 1H) 7.77 (d, J=2.57Hz, 1H) 7.75 (d, J=8.09 Hz, 1H) 7.45 (d, J=8.46 Hz, 1H) 7.33 (d, J=15.81Hz, 1H) 7.15 (d, J=2.57 Hz, 1H) 7.00 (d, J=16.18 Hz, 1H) 6.56 (d, J=2.21Hz, 1H) 6.44 (dd, J=8.46, 2.21 Hz, 1H) 5.66 (dd, J=7.91, 2.02 Hz, 1H)5.56 (s, 2H) 3.78 (s, 3H) 2.97 (s, 3H) 1.37 (s, 9H).

Example 36 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-2-fluorophenyl)methanesulfonamideCompound IB-L1-1.5

Part A. Preparation of (3-fluoro-4-nitrophenyl)methanol.

To a solution of 3-fluoro-4-nitrobenzoic acid (2.0 g, 10.8 mmol) in THF(50 ml) at 0° C. was added BH₃.Me₂S complex (2.215 ml, 22.15 mmol)drop-wise. The mixture was stirred at 0° C. for 3 h, and was thenstirred at 65° C. for 18 h. To the cooled mixture was added ice (50 g),followed by 1 N aq. HCl (100 ml), and the resulting mixture wasextracted with EtOAc (200 ml). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to provide the title compound as awhite solid (1.79 g, 97%).

Part B. Preparation of 4-(bromomethyl)-2-fluoro-1-nitrobenzene.

A solution of the product from Part A (1.79 g, 10.46 mmol),N-bromosuccinimide (2.234 g, 12.55 mmol) and triphenylphosphine (3.29 g,12.55 mmol) in CH₂Cl₂ (100 ml) and THF (50 ml) was stirred at roomtemperature for 3 h. The mixture was partitioned between H₂O (200 ml)and EtOAc (400 ml), and the organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel using 1:1 EtOAc:hexanes as theeluent to give the title compound (1.14 g, 47%).

Part C. Preparation of diethyl 3-fluoro-4-nitrobenzylphosphonate.

The product from Part B (1.25 g, 5.34 mmol) was subjected to theconditions described for Example 6, Part B to provide the title product(0.75 g, 48%).

Part D. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-2-fluorophenyl)methanesulfonamide.

The product from Part C (0.193 g, 0.662 mmol) was subjected to theconditions described for Example 13A, Part E, Part F, and Part G toprovide the title product as a colorless solid (15 mg, 5%). ¹H NMR (300MHz, DMSO-d₆) δ 11.43(s, 1H), 9.67 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.62(m, 2H), 7.41 (m, 2H), 7.38 (m, 1H), 7.23 (m, 2H), 5.66 (dd, J=8.0, 2.0Hz, 1H), 3.80 (s, 3H), 3.05 (s, 3H), 1.38 (s, 9H).

Example 37 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-2-fluoro-5-methylphenyl)methanesulfonamideCompound IB-L1-1.15

Part A. Preparation ofN-(4-bromo-2-fluoro-5-methylphenyl)methanesulfonamide.

To a solution of 4-bromo-2-fluoro-5-methylaniline (2.04 g, 10.0 mmol) inanhydrous CH₂Cl₂ (20 ml) and pyridine (3.23 ml, 40.0 mmol) was addedmethanesulfonyl chloride (0.86 ml, 11.0 mmol) and the resulting mixturewas stirred at room temperature for 2 h. Solvent was removed in vacuo,and the residue was partitioned between EtOAc and 1M aq. HCl. Theorganic layer was washed with saturated aqueous NaHCO₃, brine and thendried over Na₂SO₄. The drying agent was filtered off, and the filtratewas concentrated to give the title compound as a solid (2.80 g, 99%).

Part B. Preparation ofN-(4-ethynyl-2-fluoro-5-methylphenyl)methanesulfonamide.

A mixture of the product from Part A (3.0 g, 10.63 mmol),triphenylphosphine (0.279 g, 1.06 mmol), trimethylsilylacetate (6.0 ml,42.5 mmol) and palladium(II) acetate (0.12 g, 0.53 mmol) intriethylamine (30 ml) and toluene (15 ml) under N₂ was heated at 80° C.for 5 h. The mixture was allowed to cool to room temperature, and waspartitioned between EtOAc and 1M aq. HCl. The organic layer was washedwith saturated NaHCO₃ and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel using a solvent gradient of 10% to 35%EtOAc in hexanes to give an oil (3.0 g, 94%). To a solution of the oil(3.0 g, 10.0 mmol) in MeOH (50 ml) was added 1M aq. NaOH (21 ml, 21.0mmol), and the resulting mixture was stirred at room temperature for 45min. The mixture was partitioned between EtOAc and 1M aq. HCl, and theorganic layer was washed with brine and dried over Na₂SO₄. The dryingagent was filtered off, and the filtrate was concentrated in vacuo togive the title compound as a solid (2.3 g, quant.).

Part C. Preparation of(E)-5-fluoro-2-methyl-4-(methylsulfonamido)styrylboronic acid.

The product from Part B (0.20 g, 0.88 mmol) was subjected to theconditions described for the preparation of Example 13B, Part B to givethe title compound (42 mg, 17%).

Part D. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)-2-fluoro-5-methylphenyl)methanesulfonamide.

The product from Part C (40 mg, 0.15 mmol) was subjected to theconditions described for the preparation of Example 13B, Part I to givethe title compound (51 mg, 83%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.42 (d,J=2.21 Hz, 1H) 9.59 (s, 1H) 7.70-7.78 (m, 2H) 7.66 (d, J=11.77 Hz, 1H)7.20-7.32 (m, 3H) 5.65 (dd, J=7.72, 2.21 Hz, 1H) 3.79 (s, 3H) 3.05 (s,3H) 2.38 (s, 3H) 1.38 (s, 9H).

Example 38 Preparation of methyl2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)-5-(methylsulfonamido)benzoateCompound IB-L5-2-1.1

To a solution of the product from Example 25 (40 mg, 0.076 mmol) in MeOH(2 ml) and THF (2 ml) was added 10% Pd/C (20 mg) and the resultingmixture was stirred at room temperature under 1 atm H₂ for 16 h. Themixture was filtered through celite and concentrated in vacuo to give asolid (27.5 mg, 68%). ¹H NMR (300 MHz, DMSO-d₆)

11.39 (s, 1H) 9.88 (s, 1H) 7.61-7.71 (m, 2H) 7.28-7.36 (m, 2H) 7.20 (d,J=2.57 Hz, 1H) 7.13 (d, J=2.94 Hz, 1H) 5.64 (d, J=7.72 Hz, 1H) 3.83 (s,3H) 3.75 (s, 3 H) 3.14 (dd, J=10.30, 5.88 Hz, 2H) 2.96 (s, 3H) 2.83-2.92(m, 2H) 1.34 (s, 9H).

Example 39 Preparation ofN-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)phenyl)methanesulfonamideCompound IB-L5-2-1.2

The product from Example 13B, Part M (200 mg, 0.426 mmol) was dissolvedin MeOH (10 ml) followed by the addition of 10% Palladium on activatedCarbon (50 mg). The resultant mixture was evacuated and a hydrogenballoon attached then stirred at room temperature for 48 h. The mixturewas then filtered through celite and the filtrate concentrated undervacuum to an oil which was dissolved in ethanol (4 ml) then a 1Nsolution of aqueous sodium hydroxide (3.8 ml, 3.8 mmol) was added andthe solution stirred at room temperature for 18 h. The ethanol was thenremoved under vacuum and a 1N solution of aqueous hydrochloric acid (4ml) was added to acidify the mixture followed by extraction with EtOAc(2×10 mL). The organic extracts were combined, dried and purified bycolumn chromatography on silica gel using 5% MeOH in CH₂Cl₂ as theeluent to provide the title compound as a colorless solid (82 mg, 41%).¹H NMR (300 MHz, DMSO-d₆)

11.39 (s, 1H), 9.60 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.23 (m, 3H), 7.17(m, 3H), 5.64 (d, J=7.7 Hz, 1H), 3.77 (s, 3H), 2.93 (s, 3H), 2.88 (br s,4H), 1.35 (s, 9H).

Example 40 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-ethoxystyryl)phenyl)methanesulfonamideCompound IB-L1-1.30

Part A. Preparation of 2-tert-butyl-4-iodophenol.

To a 250 mL round-bottom flask was added 2-tert-butylphenol (3.76 g, 25mmol) in MeOH (50.0 ml) to give a colorless solution. Sodium hydroxide(1.200 g, 30.0 mmol) was added and the mix was stirred until thehydroxide was completely dissolved. The solution was cooled to 0° C. andtreated with sodium iodide (1.75 g, 11.6 mmol) followed by drop-wiseaddition of 10% sodium hypochlorite solution (7.2 ml, 11.6 mmol). Theaddition of sodium iodide followed by sodium hypochlorite was repeatedtwice and the mixture was stirred at 0° C. for 30 min. The mixture wastreated with 10% w/w solution of sodium thiosulfate, stirred for 30 minand treated with concentrated HCl dropwise to a constant pH of 1. Themixture was extracted 3× with EtOAc. The extracts were combined, washedwith brine, dried (MgS04), filtered and concentrated. The crude oil wasflash chromatographed on an Isco 80 g silica cartridge eluting withhexane to >4:1 hexane/EtOAc to give a yellow oil (5.2 g, 75%).

Part B. Preparation of 2-bromo-6-tert-butyl-4-iodophenol.

To a 250 mL round-bottom flask was added the product from Part A (40.8g, 17.38 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (2.61 g, 9.13 mmol)in chloroform (87 ml) to give an orange solution. The reaction mixturewas stirred for 2 h resulting in a black solution that was washed withwater, brine, dried (Na₂SO₄) and concentrated. The black oil was flashchromatographed on a 120 g Isco silica cartridge eluting with hexane togive a pinkish solid (4.84 g, 78%).

Part C. Preparation of 1-bromo-3-tert-butyl-2-ethoxy-5-iodobenzene.

To a 50 mL round-bottom flask was added the product from Part B (888 mg,2.5 mmol), ethyl iodide (409 mg, 2.63 mmol), and potassium carbonate(415 mg, 3.00 mmol) in acetone (12 ml) to give a green suspension. Themixture was heated at reflux for 16 h, cooled and concentrated. Theresidue was partitioned between water and EtOAc. The organic layer waswashed twice with brine, dried over Na₂SO₄, filtered and concentrated toa red oil. The oil was flash chromatographed on an Isco 40 g silicacartridge eluting with hexane to give a clear oil (820 mg, 86%).

Part D. Preparation of1-(3-bromo-5-tert-butyl-4-ethoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

In a 20 mL microwave tube under nitrogen flush was added the productfrom Part C (0.4 g, 1.044 mmol), 1H-Pyrimidine-2,4-dione (0.140 g, 1.253mmol), and potassium phosphate tribasic (0.465 g, 2.193 mmol) in DMSO (5ml) to give a colorless suspension. N-(2-cyanophenyl)picolinamide (0.047g, 0.209 mmol) was added and the mix was sparged with nitrogen for 10min. Copper(I) iodide (0.020 g, 0.104 mmol) was added and the mix wassparged once again for 10 min, placed under nitrogen and heated at 60°C. for 18 h. The mixture was cooled and partitioned between EtOAc andwater adjusting the pH to 1 with HCl. The aqueous layer was extracted 2×with EtOAc. The organics were combined, washed with water, saturatedNaHCO₃, and saturated NaCl. The organic layer was dried (Na₂SO₄),stirred with 3-mercaptopropyl functionalized silica for 1 h, filteredand concentrated. The crude product was purified by chromatography on anIsco 12 g silica cartridge eluting with 2% MeOH in CH₂Cl₂ to give awhite powder (266 mg, 69%).

Part E. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-ethoxystyryl)phenyl)methanesulfonamide.

A mixture of the product from Part D (55.1 mg, 0.15 mmol), the productfrom Example 13B, Part B (36.2 mg, 0.150 mmol), potassium phosphatetribasic (63.7 mg, 0.300 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (4.89 mg,7.50 μmol) in THF (3 ml) water (1 ml) was sparged for 10 min withnitrogen, and then sealed and heated at 50° C. for 4 h. The mixture wascooled to room temperature and diluted into EtOAc. The EtOAc layer waswashed with 1M HCl, saturated NaHCO3, saturated NaCl, dried (Na₂SO₄) andtreated simultaneously with mercaptopropyl silica gel, filtered andconcentrated. The crude product was purified by column chromatography onsilica gel using 2% MeOH in CH₂Cl₂ as the eluent to give the titlecompound as a solid (40 mg, 55%) m.p. 265-266° C. ¹H NMR (300 MHz,DMSO-d₆) δ 11.42 (s, 1H) 9.87 (s, 1H) 7.76 (d, J=8.09 Hz, 1H) 7.55-7.66(m, 3 H) 7.17-7.27 (m, 5H) 5.65 (dd, J=7.72, 1.47 Hz, 1H) 3.89 (q,J=6.74 Hz, 2H) 3.02 (s, 3H) 1.45 (t, J=6.99 Hz, 3H) 1.39 (s, 9H).

The following compounds were prepared utilizing the above discussion:

(E)-N-(4-(1-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)prop-1-en-2-yl)phenyl)methanesulfonamide (compound IA-L1-1.6). ¹H NMR(300 MHz, DMSO-d₆) δ 2.14 (s, 3 H) 2.70 (t, J=6.62 Hz, 2H) 3.01 (s, 3H)3.68 (s, 3H) 3.78 (t, J=6.62 Hz, 2H) 6.82 (s, 1H) 7.10-7.17 (m, 2H) 7.23(d, J=8.46 Hz, 2H) 7.59 (d, J=8.46 Hz, 2H) 9.78 (s, 1H) 10.32 (s, 1H).

(Z)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide(compound IA-L1-1.10). ¹H NMR (300 MHz, DMSO-d₆) δ 10.23 (s, 1H) 9.74(s, 1H) 7.23 (d, J=8.46 Hz, 2H) 7.13 (d, J=2.57 Hz, 1H) 7.06 (d, J=8.82Hz, 2H) 6.92 (d, J=2.57 Hz, 1H) 6.54-6.67 (m, 2H) 3.78 (s, 3H) 3.57 (t,J=6.62 Hz, 2H) 2.96 (s, 3H) 2.60 (t, J=6.80 Hz, 2H) 1.34 (s, 9H).

(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)-N-(methylsulfonyl)acetamide(compound IA-L1-1.11). ¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H) 7.77(d, J=8.46 Hz, 2H) 7.56 (d, J=2.21 Hz, 1H) 7.39-7.50 (m, 3H) 7.25 (d,J=16.55 Hz, 1H) 7.19 (d, J=2.57 Hz, 1H) 3.74-3.85 (m, 5H) 3.54 (s, 3H)2.72 (t, J=6.62 Hz, 2H) 1.94 (s, 3H) 1.38 (s, 9H).

(E)-1-(3-(4-aminostyryl)-5-tert-butyl-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione(compound IA-L1-1.13). ¹H NMR (300 MHz, DMSO-d₆) δ 1.36 (s, 9H) 2.70 (t,J=6.62 Hz, 2H) 3.74 (s, 3H) 3.77 (t, J=6.62 Hz, 2H) 5.34 (s, 1H) 6.57(d, J=8.46 Hz, 2H) 6.98 (s, 1H) 7.07 (d, J=2.21 Hz, 1H) 7.17 (s, 2H)7.30 (d, J=8.09 Hz, 2H) 7.45 (d, J=2.21 Hz, 1H) 10.32 (s, 1H).

(Z)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide(compound IA-L1-1.20). ¹H NMR (500 MHz, DMSO-d₆): δ ppm 1.37 (s, 9H),2.71 (t, J=6.7 Hz, 2H), 3.01 (s, 3H), 3.75 (s, 3H), 3.79 (t, J=6.6 Hz,2H), 7.13 (d, J=16.5 Hz, 1H), 7.15 (d, J=2.4 Hz, 2H), 7.23 (d, J=8.5 Hz,2H), 7.25 (d, J=16.5 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.6 Hz,2H), 9.80 (bs, 1H), 10.30 (s, 1H).

N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)1-fluorovinyl)phenyl)methanesulfonamide (compound IA-L1-1.21). (racemicmixture (1:1) of compounds IA-L1-1.4 and IA-L1-1.5).

(E)-1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione(compound IA-L1-1.22).

1-{3-tert-butyl-5-[(Z)-2-chloro-2-(4-nitro-phenyl)-vinyl]-4-methoxy-phenyl}-dihydropyrimidine-2,4-dione(compound IA-L1-1.23).

1-{3-tert-butyl-4-methoxy-5-[(E)-2-(4-nitro-phenyl)-propenyl]-phenyl}-dihydro-pyrimidine-2,4-dione(compound IA-L1-1.24).

1-{3-tert-Butyl-5-[(E)-2-(4-nitro-phenyl)-vinyl]-phenyl}-dihydro-pyrimidine-2,4-dione(compound IA-L1-1.25). ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (s, 9H)2.70-2.77 (m, 2H) 3.84 (t, J=6.80 Hz, 2H) 7.33 (s, 1H) 7.49 (d, J=4.04Hz, 2H) 7.56 (d, J=5.88 Hz, 2H) 7.89 (d, J=8.82 Hz, 2H) 8.25 (d, J=8.82Hz, 2H) 10.40 (s, 1H)

N-(4-{(E)-2-[3-tert-Butyl-5-(dioxo-tetrahydro-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-3-methoxy-phenyl)-methanesulfonamide(compound IA-L1-1.27). ¹H NMR (300 MHz, DMSO-D6) δ ppm 10.33 (s, 1H)9.86 (s, 1H) 7.64 (d, J=8.46 Hz, 1H) 7.45 (d, J=2.21 Hz, 1H) 7.26 (s,2H) 7.12 (d, J=2.21 Hz, 1H) 6.89 (s, 1H) 6.85 (dd, J=8.46, 1.84 Hz, 1H)3.84 (s, 3H) 3.78 (t, J=6.80 Hz, 2H) 3.74 (s, 3H) 3.04 (s, 3H) 2.71 (t,J=6.62 Hz, 2H) 1.37 (s, 9H)

N-(4-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-3-formyl-phenyl)-methanesulfonamide(compound IB-L1-1.6). ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.39 (s, 9H) 3.07(s, 3H) 3.81 (s, 3H) 5.66 (dd, J=7.72, 2.21 Hz, 1H) 7.26 (d, J=2.57 Hz,1H) 7.30 (d, J=16.18 Hz, 1H) 7.51 (dd, J=8.64, 2.39 Hz, 1H) 7.69 (d,J=2.57 Hz, 1H) 7.73-7.78 (m, 2H) 7.97 (d, J=8.82 Hz, 1H) 8.06 (d,J=16.18 Hz, 1H) 10.15 (s, 1H) 10.45 (s, 1H) 11.43 (d, J=2.21 Hz, 1H)

N-[4-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-3-(hydroxyimino-methyl)-phenyl]-methanesulfonamide(compound IB-L1-1.8). ¹H NMR (300 MHz, DMSO-d₆) δ 1.38 (s, 9H) 3.03 (s,3H) 3.79 (s, 3H) 5.66 (dd, J=7.91, 2.02 Hz, 1H) 7.16 (d, J=15.81 Hz, 1H)7.22 (d, J=2.57 Hz, 1H) 7.26 (dd, J=8.64, 2.39 Hz, 1H) 7.59 (d, J=16.18Hz, 1H) 7.63 (d, J=2.21 Hz, 1H) 7.73-7.83 (m, 3H) 8.64 (s, 1H) 9.96 (s,1H) 11.42 (d, J=2.21 Hz, 1H) 11.50 (s, 1H).

2-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonylamino-N-(2-methoxy-ethyl)-benzamide(compound IB-L1-1.9). ¹H NMR (300 MHz, DMSO-D6) δ 1.38 (s, 9H) 3.05 (s,3H) 3.20 (s, 3H) 3.37-3.49 (m, 4H) 3.78 (s, 3H) 5.64 (d, J=7.72 Hz, 1H)7.15 (d, J=2.57 Hz, 1H) 7.20 (d, J=2.57 Hz, 1H) 7.24 (s, 2H) 7.28 (dd,J=8.46, 2.21 Hz, 1H) 7.42 (d, J=2.57 Hz, 1H) 7.73 (d, J=7.72 Hz, 1H)7.87 (d, J=8.82 Hz, 1H) 8.49 (t, J=5.15 Hz, 1H) 9.99 (s, 1H) 11.42 (s,1H).

2-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonylamino-benzoicacid ethyl ester (compound IB-L1-1.11). ¹H NMR (300 MHz, DMSO-d₆) δ 1.31(t, J=7.17 Hz, 3H) 1.38 (s, 9H) 3.05 (s, 3H) 3.79 (s, 3H) 4.33 (q,J=7.23 Hz, 2H) 5.65 (dd, J=7.72, 2.21 Hz, 1H) 7.15-7.25 (m, 2H) 7.46(dd, J=8.64, 2.39 Hz, 1H) 7.52 (d, J=2.57 Hz, 1H) 7.68 (d, J=2.57 Hz,1H) 7.71-7.81 (m, 2H) 7.90 (d, J=8.46 Hz, 1H) 10.06 (s, 1H) 11.42 (d,J=1.84 Hz, 1H).

N-(4-{(E)-2-[3-tert-Butyl-2-chloro-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-phenyl]-vinyl}-phenyl)-methanesulfonamide(compound IB-L1-1.12). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49 (s, 9 H)3.02 (s, 3H) 5.69 (d, J=7.72 Hz, 1H) 7.22 (m, 3H) 7.41 (d, J=2.21 Hz,1H) 7.51 (d, J=16.18 Hz, 1H) 7.59 (d, J=8.82 Hz, 2H) 7.78 (d, J=2.21 Hz,1H) 7.80 (d, J=8.09 Hz, 1H) 9.90 (s, 1H) 11.47 (s, 1H).

2-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonylamino-N,N-dimethyl-benzamide(compound IB-L1-1.14). ¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (s, 9H) 2.76 (s,3H) 3.03 (s, 3H) 3.05 (s, 3H) 3.76 (s, 3H) 5.64 (dd, J=7.91, 1.65 Hz,1H) 6.95 (d, J=16.55 Hz, 1H) 7.02 (d, J=2.21 Hz, 1H) 7.17-7.25 (m, 2H)7.27 (dd, J=8.64, 2.39 Hz, 1H) 7.48 (d, J=2.57 Hz, 1H) 7.74 (d, J=8.09Hz, 1H) 7.82 (d, J=8.82 Hz, 1H) 10.03 (s, 1H) 11.39-11.43 (m, 1H).

2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonylamino-N-methyl-benzamide(compound IB-L1-1.17). ¹H NMR (300 MHz, DMSO-d₆) δ 1.38 (s, 9H) 2.77 (d,J=4.41 Hz, 3H) 3.06 (s, 3H) 3.77 (s, 3H) 5.64 (dd, J=7.72, 1.84 Hz, 1H)7.16-7.33 (m, 5H) 7.43 (d, J=2.21 Hz, 1H) 7.73 (d, J=7.72 Hz, 1H) 7.84(d, J=8.46 Hz, 1H) 8.37 (q, J=4.41 Hz, 1H) 10.00 (s, 1H) 11.40 (d,J=1.84 Hz, 1H).

2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-N-(1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-yl)-5-methanesulfonylamino-N-methyl-benzamide(compound IB-L1-1.18). ¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (s, 9H)2.17-2.47 (m, 2H) 2.70 (s, 3H) 3.06 (s, 3H) 3.15-3.31 (m, 2H) 3.36-3.51(m, 2H) 3.77 (s, 3H) 5.37 (dt, J=17.74, 8.96 Hz, 1H) 5.65 (dd, J=7.91,2.02 Hz, 1H) 6.93 (d, J=16.18 Hz, 1H) 7.05 (d, J=2.21 Hz, 1H) 7.19-7.35(m, 3H) 7.50 (d, J=2.57 Hz, 1H) 7.76 (d, J=8.09 Hz, 1H) 7.87 (d, J=8.82Hz, 1H) 10.04 (s, 1H) 11.38 (d, J=2.21 Hz, 1H).

N-(4-{(E)-2-[3-tert-butyl-5-(5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxyphenyl]-vinyl}-phenyl)-methanesulfonamide(Compound IB-L1-1.20). ¹H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1H)9.77 (s, 1H) 7.53 (d, J=8.09 Hz, 1H) 7.23 (d, J=8.46 Hz, 2H) 7.17 (d,J=2.57 Hz, 1H) 7.06 (d, J=8.82 Hz, 2H) 7.01 (d, J=2.57 Hz, 1H) 6.53-6.71(m, 2H) 5.56 (d, J=7.72 Hz, 1H) 3.81 (s, 3H) 2.96 (s, 3H) 1.35 (s, 9H)

2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonylamino-benzamide(compound IB-L1-1.21). ¹H NMR (300 MHz, DMSO-d₆) δ 1.38 (s, 9H) 3.07 (s,3H) 3.78 (s, 3H) 5.64 (d, J=7.72 Hz, 1H) 7.18-7.34 (m, 5H) 7.43 (d,J=2.21 Hz, 1H) 7.54 (s, 1H) 7.73 (d, J=7.72 Hz, 1H) 7.84 (d, J=8.46 Hz,1H) 7.93 (s, 1H).

N-(3-(azetidine-1-carbonyl)-4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-phenyl)-methanesulfonamide(compound (compound IB-L1-1.22). ¹H NMR (300 MHz, DMSO-d₆) δ 1.38 (s,9H) 3.07 (s, 3H) 3.78 (s, 3H) 5.64 (d, J=7.72 Hz, 1H) 7.18-7.34 (m, 5H)7.43 (d, J=2.21 Hz, 1H) 7.54 (s, 1H) 7.73 (d, J=7.72 Hz, 1H) 7.84 (d,J=8.46 Hz, 1H) 7.93 (s, 1H).

2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonylamino-N-(2-methoxy-ethyl)-N-methyl-benzamide(compound IB-L1-1.24). ¹H NMR (300 MHz, DMSO-d₆) δ 1.40 (s, 9H) 2.81 (s,3H) 3.07 (s, 3H) 3.23 (s, 3H) 3.29 (t, J=5.33 Hz, 1H) 3.39 (t, J=4.96Hz, 1H) 3.62 (t, J=4.78 Hz, 2H) 3.82 (s, 3H) 5.68 (d, J=8.09 Hz, 1H)6.96-7.07 (m, 1H) 7.09-7.17 (m, 1H) 7.23-7.38 (m, 3H) 7.49 (dd, J=16.55,2.57 Hz, 1H) 7.71-7.76 (m, 1H) 7.83-7.94 (m, 1H).

N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-3-isopropoxymethyl-phenyl)-methanesulfonamide(compound IB-L1-1.25). ¹H NMR (300 MHz, DMSO-d₆) δ 1.16 (d, J=5.88 Hz,6H) 1.38 (s, 9H) 3.01 (s, 3H) 3.69 (dt, J=12.13, 6.07 Hz, 1H) 3.79 (s,3H) 4.59 (s, 2H) 5.65 (dd, J=7.91, 2.02 Hz, 1H) 7.13-7.29 (m, 4H)7.32-7.40 (m, 1H) 7.59 (d, J=2.57 Hz, 1H) 7.75 (d, J=8.09 Hz, 2H) 9.86(s, 1H) 11.43 (d, J=1.84 Hz, 1H).

N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-3-(pyrrolidine-1-carbonyl)-phenyl]-methanesulfonamide(compound IB-L1-1.27). ¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (s, 9H)1.73-1.89 (m, 4H) 3.03-3.12 (m, 5H) 3.51 (t, J=6.80 Hz, 2H) 3.76 (s, 3H)5.64 (dd, J=7.91, 2.02 Hz, 1H) 6.99-7.06 (m, 1H) 7.08 (d, J=2.21 Hz, 1H)7.19-7.31 (m, 3H) 7.46 (d, J=2.57 Hz, 1H) 7.75 (d, J=8.09 Hz, 1H) 7.82(d, J=8.82 Hz, 1H) 10.01 (s, 1H) 11.41 (d, J=2.21 Hz, 1H).

N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-3-(3-hydroxy-azetidin-1-ylmethyl)-phenyl]-methanesulfonamide(compound IB-L1-1.29). ¹H NMR (300 MHz, DMSO-d₆) δ 1.38 (s, 9H)2.78-2.85 (m, 2H) 2.99 (s, 3H) 3.50-3.58 (m, 2H) 3.71 (s, 2H) 3.79 (s,3H) 4.19 (td, J=12.41, 6.07 Hz, 1H) 5.29 (d, J=6.25 Hz, 1H) 5.66 (d,J=8.09 Hz, 1H) 7.10-7.18 (m, 2H) 7.20 (t, J=2.21 Hz, 2H) 7.35-7.42 (m,1H) 7.63 (d, J=2.57 Hz, 1H) 7.69 (d, J=8.46 Hz, 1H) 7.76 (d, J=7.72 Hz,1H) 9.78 (s, 1H) 11.42 (s, 1H).

N-(4-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-3-pyrrolidin-1-ylmethyl-phenyl)-methanesulfonamide(compound IB-L1-1.33). ¹H NMR (500 MHz, DMSO-d₆) δ 1.40 (s, 9H)1.72-1.95 (m, 4H) 2.84 (s, 2H) 2.88-2.98 (m, 2H) 3.01 (s, 3H) 3.81 (s,3H) 3.86-4.23 (m, 2H) 5.63 (d, J=7.81 Hz, 1H) 7.17 (d, J=15.63 Hz, 1H)7.21-7.28 (m, 2H) 7.32-7.38 (m, 1H) 7.47 (d, J=16.11 Hz, 1H) 7.53-7.59(m, 1H) 7.61 (d, J=7.81 Hz, 1H) 7.70 (d, J=6.35 Hz, 1H) 9.42 (s, 1H)10.88 (s, 1H).

N-(4-{(Z)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-methoxy-phenyl]-vinyl}-phenyl)-methanesulfonamide(compound IB-L1-1.34 ¹H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1H) 9.77(s, 1H) 7.53 (d, J=8.09 Hz, 1H) 7.23 (d, J=8.46 Hz, 2H) 7.17 (d, J=2.57Hz, 1H) 7.06 (d, J=8.82 Hz, 2H) 7.01 (d, J=2.57 Hz, 1H) 6.53-6.71 (m,2H) 5.56 (d, J=7.72 Hz, 1H) 3.81 (s, 3H) 2.96 (s, 3H) 1.35 (s, 9H)

N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl)phenyl)methanesulfonamide (compound IA-L5-2-1.2). ¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (s,9H) 2.69 (t, J=6.62 Hz, 2H) 2.83 (s, 4H) 2.91 (s, 3H) 3.75 (t, J=6.62Hz, 2H) 6.99-7.21 (m, 7H) 9.60 (s, 1H) 10.31 (s, 1H).

methyl2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)-5-(methylsulfonamido)benzoate (compound IB-L5-2-1.1). ¹H NMR (300MHz, DMSO-d₆) δ 1.34 (s, 9H) 2.83-2.92 (m, 2H) 2.96 (s, 3H) 3.14 (dd,J=10.30, 5.88 Hz, 2H) 3.75 (s, 3H) 3.83 (s, 3H) 5.64 (d, J=7.72 Hz, 1H)7.13 (d, J=2.94 Hz, 1H) 7.20 (d, J=2.57 Hz, 1H) 7.28-7.36 (m, 2H)7.61-7.71 (m, 2H) 9.88 (s, 1H) 11.39 (s, 1H)

N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)phenyl)methanesulfonamide(compound IB-L5-2-1.2). ¹H NMR (300 MHz, DMSO-d6): δ 11.39 (s, 1H), 9.60(s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.23 (m, 3H), 7.17 (m, 3H), 5.64 (d,J=7.7 Hz, 1H), 3.77 (s, 3H), 2.93 (s, 3H), 2.88 (bs, 4H), 1.35 (s, 9H)

The following compounds can be prepared utilizing the above discussion:

TABLE A

IA-L1-1.2

IA-L1-1.7

IA-L1-1.15

HCV Polymerase Inhibition Assay

Either two-fold serial dilutions (fractional inhibition assay) or anarrower range of dilutions spanning the IC₅₀ of the inhibitor (tightbinding assay) of the inhibitors were incubated with 20 mM Tris-Cl pH7.4, 2 mM MnCl₂, 1 mM dithiothreitol, 1 mM ethylene diamine tetraaceticacid (EDTA), 60 to 125 μM GTP and 20 to 50 nM Δ21 NS5B (HCV Strain 1B(BK, Genbank accession number M58335, or H77, Genbank accession numberAF011751)) for 15 min at room temperature. The reaction was initiated bythe addition of 20 μM CTP, 20 μM ATP, 1 μM ³H-UTP (10 mCi/umol), 5 nMtemplate RNA and 0.1 U/μl RNase inhibitor (RNasin, Promega), and allowedto proceed for 2 to 4 h at room temperature. Reaction volume was 50 μl.The reaction was terminated by the addition of 1 volume of 4 mM sperminein 10 mM Tris-Cl pH 8.0, 1 mM EDTA. After incubation for at least 15 minat room temperature, the precipitated RNA was captured by filteringthrough a GF/B filter (Millipore) in a 96 well format. The filter platewas washed three times with 200 μl each of 2 mM spermine, 10 mM Tris-ClpH 8.0, 1 mM EDTA, and 2 times with ethanol. After air-drying, 30 μl ofMicroscint 20 scintillation cocktail (Packard) was added to each well,and the retained cpm were determined by scintillation counting. IC₅₀values were calculated by a two-variable nonlinear regression equationusing an uninhibited control and a fully inhibited control sample todetermine the minimum and maximum for the curve. Tight-binding assayswere performed on those compounds exhibiting IC₅₀ values less than 0.005μM in the fractional inhibition assay in order to more precisely measurethe IC₅₀ values. Retained cpm were plotted vs. inhibitor concentrationand fit to equation 1 using non-linear regression (ref. 1) to obtain theIC₅₀ values:

Retained cpm=A[sqrt{(IC ₅₀ +I _(t) −E _(t)){circumflex over (α)}2+4*IC₅₀ *E _(t)}−(IC ₅₀ +I _(t) −E _(t))]  (eqn 1)

where A=Vmax[S]/2(Km+[S]); It=total inhibitor concentration and Et=totalactive concentration of enzyme.

Ref. Morrison, J. F. and S. R. Stone. 1985. Approaches to the study andanalysis of the inhibition of enzymes by slow- and tight-bindinginhibitors. Comments Mol. Cell. Biophys. 2: 347-368.

The sequence of the template RNA used was: 5′-GGGCGAAUUG GGCCCUCUAGAUGCAUGCUC GAGCGGCCGC CAGUGUGAUG GAUAUCUGCA GAAUUCGCCC UUGGUGGCUCCAUCUUAGCC CUAGUCACGG CUAGCUGUGA AAGGUCCGUG AGCCGCUUGA CUGCAGAGAGUGCUGAUACU GGCCUCUCUG CAGAUCAAGUC-3′

When tested by the above method, the compounds of this invention inhibitHCV polymerase 1A and/or 1B. The legend in the table below is asfollows: A—IC₅₀≦0.01 uM; B—0.1 uM≧IC₅₀>0.01 uM; C—1 uM≧IC₅₀>0.1 uM; andD—IC₅₀>1 uM; ND—not determined.

TABLE IC₅₀ compound 1a 1b compound 1a 1b IA-L1-1.3 A A IA-L1-1.4 A AIA-L1-1.5 A B IA-L1-1.6 A B IA-L1-1.9 A B IA-L1-1.10 B B IA-L1-1.11 B BIA-L1-1.12 C C IA-L1-1.13 C C IA-L1-1.14 D D IA-L1-1.16 A A IA-L1-1.17 BB IA-L1-1.18 C C IA-L1-1.20 A B IA-L1-1.21 B B IA-L1-1.22 C C IA-L1-1.23C C IA-L1-1.24 D D IA-L1-1.25 D D IA-L1-1.26 B B IA-L1-1.27 A BIB-L1-1.1 A A IB-L1-1.2 B B IB-L1-1.4 A A IB-L1-1.5 A A IB-L1-1.6 A BIB-L1-1.7 A B IB-L1-1.8 A B IB-L1-1.9 A B IB-L1-1.10 A B IB-L1-1.11 A BIB-L1-1.12 A B IB-L1-1.13 A B IB-L1-1.14 A B IB-L1-1.15 A B IB-L1-1.16 AB IB-L1-1.17 A B IB-L1-1.18 A B IB-L1-1.19 A B IB-L1-1.20 A B IB-L1-1.21A B IB-L1-1.22 B B IB-L1-1.23 B B IB-L1-1.24 B B IB-L1-1.25 B BIB-L1-1.26 B B IB-L1-1.27 B B IB-L1-1.28 B B IB-L1-1.29 B B IB-L1-1.30 BB IB-L1-1.31 B C IB-L1-1.32 C C IB-L1-1.33 C C IB-L1-1.34 D D IB-L1-1.45A B IB-L1-1.46 B B IB-L1-1.47 B B IB-L1-1.48 B B IB-L1-1.49 B CIB-L1-1.50 B B IB-L1-1.51 B B IB-L1-1.52 C C IB-L1-1.53 D D IB-L1-1.55 DD IA-L5-2-1.1 B B IA-L5-2-1.2 B B IB-L5-2-1.1 A B IB-L5-2-1.2 B BIA-L8-1.1 C C

HCV Polymerase Replicon Assay

Two stable subgenomic replicon cell lines were used for compoundcharacterization in cell culture: one derived from genotype 1a-H77 andone derived from genotype 1b-Con1 (obtained from Apath, LLC, St. Louis,Mo.). All replicon constructs were bicistronic subgenomic repliconssimilar to those described by Bartenschlager and coworkers (Lohmann etal., Replication of Subgenomic Hepatitis C Virus RNAs in a Hepatoma CellLine, SCIENCE 285:110-3 (1999)). The genotype 1a replicon constructcontains NS3-NS5B coding region derived from the H77 strain of HCV(1a-H77) (Blight et al., Efficient Replication of Hepatitis C VirusGenotype 1a RNAs in Cell Culture, J. VIROL. 77:3181-90 (2003)). Thereplicon also has a firefly luciferase reporter and a neomycinphosphotransferase (Neo) selectable marker. These two coding regions,separated by the FMDV 2a protease, comprise the first cistron of thebicistronic replicon construct, with the second cistron containing theNS3-NS5B coding region with addition of adaptive mutations E1202G,K1691R, K2040R and S22041. The 1b-Con1 replicon construct is identicalto the 1a-H77 replicon, except that the NS3-NS5B coding region wasderived from the 1b-Cont strain, and the adaptive mutations are E1202G,T1280I and S2204I. Replicon cell lines were maintained in Dulbecco'smodified Eagles medium (DMEM) containing 10% (v/v) fetal bovine serum(FBS), 100 IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen), and200 mg/ml G418 (Invitrogen).

The inhibitory effects of compounds on HCV replication were determinedby measuring activity of the luciferase reporter gene. Briefly,replicon-containing cells were seeded into 96 well plates at a densityof 5000 cells per well in 100 ul DMEM containing 5% FBS. 16-24 h later,the compounds were diluted in dimethyl sulfoxide (DMSO) to generate a200× stock in a series of eight half-log dilutions. The dilution serieswas then further diluted 100-fold in the medium containing 5% FBS.Medium with the inhibitor was added to the overnight cell culture platesalready containing 100 ul of DMEM with 5% FBS. In assays measuringinhibitory activity in the presence of human plasma, the medium from theovernight cell culture plates was replaced with DMEM containing 40%human plasma and 5% FBS. The cells were incubated for three days in thetissue culture incubators and were then lysed for RNA extraction. Forthe luciferase assay, 30 ul of Passive Lysis buffer (Promega) was addedto each well, and then the plates were incubated for 15 min with rockingto lyse the cells. Luciferin solution (50 to 100 ul, Promega) was addedto each well, and luciferase activity was measured with a Victor IIluminometer (Perkin-Elmer). The percent inhibition of HCV RNAreplication was calculated for each compound concentration and the EC₅₀value was calculated using nonlinear regression curve fitting to the4-parameter logistic equation and GraphPad Prism 4 software.

When tested by the above method, the compounds of this invention inhibitHCV polymerase 1A and/or 1B. The legend in the table below is asfollows: A—EC₅₀≦0.01 uM; B—0.1 uM≧EC₅₀>0.01 uM; C—1 uM≧EC₅₀>0.1 uM; andD—EC₅₀>1 uM; ND—not determined.

TABLE EC₅₀ compound 1a 1b compound 1a 1b IA-L1-1.3 B A IA-L1-1.4 A AIA-L1-1.5 B A IA-L1-1.6 B B IA-L1-1.9 B A IA-L1-1.10 B B IA-L1-1.11 A AIA-L1-1.12 C C IA-L1-1.13 D C IA-L1-1.14 D D IA-L1-1.16 B B IA-L1-1.17 BB IA-L1-1.18 C C IA-L1-1.20 B B IA-L1-1.21 A A IA-L1-1.22 D C IA-L1-1.23D D IA-L1-1.24 D D IA-L1-1.25 ND ND IA-L1-1.26 B B IA-L1-1.27 B AIB-L1-1.1 A A IB-L1-1.2 ND B IB-L1-1.4 B A IB-L1-1.5 B A IB-L1-1.6 A AIB-L1-1.7 A A IB-L1-1.8 B A IB-L1-1.9 B A IB-L1-1.10 A A IB-L1-1.11 B AIB-L1-1.12 B B IB-L1-1.13 B A IB-L1-1.14 B A IB-L1-1.15 A A IB-L1-1.16 CB IB-L1-1.17 B A IB-L1-1.18 B B IB-L1-1.19 B A IB-L1-1.20 B A IB-L1-1.21B A IB-L1-1.22 B A IB-L1-1.23 C A IB-L1-1.24 B A IB-L1-1.25 B AIB-L1-1.26 B A IB-L1-1.27 B A IB-L1-1.28 A A IB-L1-1.29 C C IB-L1-1.30 CB IB-L1-1.31 D D IB-L1-1.32 C B IB-L1-1.33 C B IB-L1-1.34 B A IB-L1-1.45B A IB-L1-1.46 C A IB-L1-1.47 C B IB-L1-1.48 C A IB-L1-1.49 D DIB-L1-1.50 C B IB-L1-1.51 D B IB-L1-1.52 D C IB-L1-1.53 ND ND IB-L1-1.55ND ND IA-L5-2-1.1 C B IA-L5-2-1.2 C C IB-L5-2-1.1 B A IB-L5-2-1.2 C BIA-L6-1.1 C B IA-L8-1.1 C C

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

1. A compound or salt thereof, wherein: the compound corresponds instructure to formula I:

is selected from the group consisting of single carbon-carbon bond anddouble carbon-carbon bond; R¹ is selected from the group consisting ofhydrogen, methyl, and nitrogen-protecting group; R² is selected from thegroup consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, andcyclobutyl; R³ is selected from the group consisting of hydrogen, halo,oxo, and methyl; R⁴ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein: (a) the amino, aminocarbonyl,and aminosulfonyl optionally are substituted with: (1) one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, and alkylsulfonyl, or (2) two substituents that,together with the amino nitrogen, form a single-ring heterocyclyl, and(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, andalkylsulfonyl, optionally are substituted with one or more substituentsindependently selected from the group consisting of halo, oxo, nitro,cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, andheterocyclyl, wherein: the amino optionally is substituted with: (1) oneor two substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or(2) two substituents that, together with the amino nitrogen, form asingle-ring heterocyclyl, and (c) the carbocyclyl and heterocyclyloptionally are substituted with up to three substituents independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halo,oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl,carbocyclyl, and heterocyclyl, wherein: the amino optionally issubstituted with: (1) one or two substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl,alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocyclylalkyl, or (2) two substituents that,together with the amino nitrogen, form a single-ring heterocyclyl; R⁵ isselected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl,alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy,carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo; L is selectedfrom the group consisting of C(R^(A))═C(R^(B)), ethylene, andcyclopropyl-1,2-ene; R^(A) and R^(B) are independently selected from thegroup consisting of hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy,C₃-C₈-cycloalkyl, and halo, wherein: the C₁-C₆-alkyl optionally issubstituted with one or more substituents independently selected fromthe group consisting of carboxy, halo, hydroxy, nitro, oxo, amino,cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, andheterocyclyl; R⁶ is selected from the group consisting ofC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl, wherein each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K); each R^(E) is independently selectedfrom the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano,amino, imino, azido, and aldehydro, wherein: the amino optionally issubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkenyl, and alkynyl; each R^(F) isindependently selected from the group consisting of alkyl, alkenyl, andalkynyl, wherein: each such substituent optionally is substituted withone or more substituents independently selected from the groupconsisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo,aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl,heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino,aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl optionallyare substituted with one or two substituents independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino, hydroxy, andalkyloxy, wherein: amino portion of the alkylsulfonylamino optionally issubstituted with a substituent selected from the group consisting ofalkyl, alkenyl, and alkynyl; each R^(G) is independently selected fromthe group consisting of carbocyclyl and heterocyclyl, wherein: each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo,aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, andaminocarbonyl, wherein: the amino, aminosulfonyl, and aminocarbonyloptionally are substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl; each R^(H) isindependently selected from the group consisting of alkyloxy,alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, andalkynylsulfonyloxy, wherein: each such substituent optionally issubstituted with one or more substituents independently selected fromthe group consisting of carboxy, hydroxy, halo, amino, nitro, azido,oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl,heterocyclyl, cyano, and aminocarbonyl, wherein: the amino,aminosulfonyl, and aminocarbonyl optionally are substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, andalkynylsulfonyl; each R¹ is independently selected from the groupconsisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, andheterocyclylcarbonyl, wherein: (a) the alkylcarbonyl, alkenylcarbonyl,and alkynylcarbonyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofcarboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, andaminocarbonyl, and (b) the aminocarbonyl optionally is substituted withone or two substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl,alkylsulfonyl, and alkylsulfonylamino, wherein: the carbocyclyl andheterocyclyl optionally are substituted with one or two substituentsindependently selected from the group consisting of halo, alkyl, andoxo; each R^(J) is independently selected from the group consisting ofcarbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino,alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino,alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino,alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,alkyloxycarbonylaminoimino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein: (a)the amino portion of such substituents optionally is substituted with asubstituent independently selected from the group consisting ofcarbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy,aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl,wherein: (1) the carbocyclyl portion of the carbocyclylalkyl and theheterocyclyl portion of the heterocyclylalkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy,alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and(2) the amino portion of the aminocarbonylalkyl optionally issubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkenyl, and alkynyl, (b) the alkyl, alkenyl,and alkynyl portion of such substituents optionally is substituted withone or more substituents independently selected from the groupconsisting of carboxy, halo, oxo, amino, alkyloxycarbonyl,alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, andcyano, wherein: the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: thealkyl optionally is substituted with one or more hydroxy; (c) thecarbocyclyl and heterocyclyl portions of such substituents optionallyare substituted with one or more substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy,alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino,wherein: the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, and alkynyl; and each R^(K) is independently selected from thegroup consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, andalkynylsulfonyl, wherein: (a) the alkylsulfonyl, alkenylsulfonyl, andalkynylsulfonyl optionally are substituted with one or more substituentsindependently selected from the group consisting of carboxy, hydroxy,halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,wherein: the amino, aminosulfonyl, and aminocarbonyl optionally aresubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkenyl, and alkynyl; and (b) theaminosulfonyl optionally is substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkenyl, andalkynyl.
 2. The compound or salt of claim 1, wherein

is a single carbon-carbon bond.
 3. The compound or salt of claim 1,wherein

is a double carbon-carbon bond.
 4. The compound or salt of claim 1,wherein R¹ is selected from the group consisting of hydrogen and methyl.5. The compound or salt of claim 1, wherein R¹ is hydrogen.
 6. Thecompound or salt of claim 1, wherein R² is selected from the groupconsisting of hydrogen, methyl, and halo.
 7. The compound or salt ofclaim 1, wherein R² is hydrogen.
 8. The compound or salt of claim 1,wherein R³ is selected from the group consisting of hydrogen and methyl.9. The compound or salt of claim 1, wherein R³ is hydrogen.
 10. Thecompound or salt of claim 1, wherein R⁴ is selected from the groupconsisting of halo, C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino,C₁-C₄-alkylsulfonyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl,wherein: (a) the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, and alkylsulfonyl, (b) the C₁-C₄-alkyl, C₂-C₄-alkenyl,and C₂-C₄-alkynyl optionally are substituted with one or moresubstituents independently selected from the group consisting of halo,oxo, hydroxy, alkyloxy, and trimethylsilyl, and (c) theC₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally aresubstituted with up to three substituents independently selected fromthe group consisting of alkyl, alkenyl, alkynyl, halo, and amino,wherein: the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, and alkylsulfonyl.
 11. The compound or salt of claim1, wherein R⁴ is selected from the group consisting of halo, alkyl,alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy,amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, andheterocyclyl.
 12. The compound or salt of claim 1, wherein R⁴ isselected from the group consisting of C₁-C₄-alkyl, C₃-C₆-carbocyclyl,and 5-6-membered heterocyclyl.
 13. The compound or salt of claim 1,wherein R⁴ is selected from the group consisting of halo, tert-butyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl.
 14. The compound orsalt of claim 1, wherein R⁴ is selected from the group consisting oftert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl.
 15. Thecompound or salt of claim 1, wherein R⁴ is alkyl.
 16. The compound orsalt of claim 1, wherein R⁴ is tert-butyl.
 17. The compound or salt ofclaim 1, wherein R⁵ is selected from the group consisting of hydrogen,hydroxy, alkyloxy, and halo.
 18. The compound or salt of claim 1,wherein R⁵ is selected from the group consisting of hydrogen, methoxy,and halo.
 19. The compound or salt of claim 1, wherein R⁵ is methoxy.20. The compound or salt of claim 1, wherein L is C(R^(A))═C(R^(B)). 21.The compound or salt of claim 1, wherein R^(A) and R^(B) areindependently selected from the group consisting of hydrogen,C₁-C₆-alkyl, C₁-C₆-alkyloxy, and halo.
 22. The compound or salt of claim1, wherein: R^(A) is hydrogen; and R^(B) is selected from the groupconsisting of hydrogen, methyl, methoxy, and halo.
 23. The compound orsalt of claim 1, wherein L is ethylene.
 24. The compound or salt ofclaim 1, wherein L is cyclopropyl-1,2-ene.
 25. The compound or salt ofclaim 1, wherein R⁶ is selected from the group consisting ofC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl, wherein each suchsubstituent is substituted with one, two, or three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K).
 26. The compound or salt of claim 1,wherein R⁶ is selected from the group consisting of C₅-C₆-carbocyclyland 5-6-membered heterocyclyl, wherein each such substituent issubstituted with one, two, or three substituents independently selectedfrom the group consisting of R^(E), R^(F), R^(I), R^(J), and R^(K). 27.The compound or salt of claim 1, wherein R⁶ is selected from the groupconsisting of C₅-C₆-carbocyclyl and 5-6-membered heterocyclyl, whereineach such substituent is substituted with one, two, or threesubstituents independently selected from the group consisting of R^(E),R^(F), and R^(J).
 28. The compound or salt of claim 1, wherein R⁶ isC₅-C₆-carbocyclyl substituted with one, two, or three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K).
 29. The compound or salt of claim 1,wherein R⁶ is C₅-C₆-carbocyclyl substituted with one, two, or threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(I), R^(J), and R^(K).
 30. The compound or salt of claim 1,wherein R⁶ is C₅-C₆-carbocyclyl substituted with one, two, or threesubstituents independently selected from the group consisting of R^(E),R^(F), and R^(J).
 31. The compound or salt of claim 1, wherein R⁶ isC₅-C₆-carbocyclyl substituted with one or two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K).
 32. The compound or salt of claim 1, wherein R⁶ isC₅-C₆-carbocyclyl substituted with one or two substituents independentlyselected from the group consisting of R^(E), R^(F), and R^(J).
 33. Thecompound or salt of claim 1, wherein R⁶ is C₅-C₆-carbocyclyl substitutedwith a substituent selected from the group consisting of R^(E), R^(F),R^(H), R^(H), R^(I), R^(J), and R^(K).
 34. The compound or salt of claim1, wherein R⁶ is C₅-C₆-carbocyclyl substituted with a substituentselected from the group consisting of R^(F) and R^(J).
 35. The compoundor salt of claim 1, wherein R⁶ is phenyl.
 36. The compound or salt ofclaim 1, wherein R⁶ is phenyl substituted with one or two substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K).
 37. The compound or salt of claim 1,wherein R⁶ is phenyl substituted with one or two substituentsindependently selected from the group consisting of R^(E), R^(F), andR^(J).
 38. The compound or salt of claim 1, wherein R⁶ is phenylsubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).
 39. The compound orsalt of claim 1, wherein R⁶ is phenyl substituted with a substituentselected from the group consisting of R^(F) and R^(J).
 40. The compoundor salt of claim 1, wherein R⁶ is phenyl substituted with R^(J).
 41. Thecompound or salt of claim 1, wherein each R^(E) is independentlyselected from the group consisting of halo, nitro, hydroxy, oxo,carboxy, cyano, amino, and imino.
 42. The compound or salt of claim 1,wherein each R^(F) is an independently selected alkyl substituted withamino, wherein the amino is substituted with alkylsulfonyl.
 43. Thecompound or salt of claim 1, wherein each R^(G) is an independentlyselected 5-6-membered heterocyclyl.
 44. The compound or salt of claim 1,wherein each R^(H) is an independently selected alkyloxy.
 45. Thecompound or salt of claim 1, wherein each R^(I) is independentlyselected from the group consisting of alkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl,and heterocyclylcarbonyl.
 46. The compound or salt of claim 1, whereineach R^(J) is independently selected from the group consisting ofcarbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino,alkyloxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, andalkylsulfonylaminoimino
 47. The compound or salt of claim 1, whereineach R^(J) is an independently selected alkylsulfonylamino.
 48. Thecompound or salt of claim 1, wherein each R^(J) is methylsulfonylamino.49. The compound or salt of claim 1, wherein each R^(K) is independentlyselected from the group consisting of aminosulfonyl and alkylsulfonyl.50. The compound or salt of claim 1, wherein: R¹ is selected from thegroup consisting of hydrogen and methyl; R² is selected from the groupconsisting of hydrogen, methyl, and halo; and R³ is selected from thegroup consisting of hydrogen and methyl.
 51. The compound or salt ofclaim 1, wherein: R¹ is hydrogen; R² is hydrogen; and R³ is hydrogen.52. The compound or salt of claim 1, wherein: R⁴ is selected from thegroup consisting of halo, C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and5-6-membered heterocyclyl, wherein: (a) the C₁-C₄-alkyl optionally issubstituted with up to three substituents independently selected fromthe group consisting of halo, oxo, hydroxy, alkyloxy, andtrimethylsilyl, and (b) the C₃-C₆-carbocyclyl and 5-6-memberedheterocyclyl optionally are substituted with one or two substituentsindependently selected from the group consisting of alkyl, halo, andalkylsulfonylamino; and R⁵ is selected from the group consisting ofhydrogen, hydroxy, alkyloxy, and halo.
 53. The compound or salt of claim1, wherein: R⁴ is tert-butyl; and R⁵ is methoxy.
 54. The compound orsalt of claim 1, wherein: R¹ is hydrogen; R² is selected from the groupconsisting of hydrogen and halo; R³ is hydrogen; R⁴ is tert-butyl; R⁵ isselected from the group consisting of hydroxy and methoxy; R^(A) ishydrogen; and R^(B) is hydrogen.
 55. The compound or salt of claim 1,wherein: R¹ is hydrogen; R² is selected from the group consisting ofhydrogen and halo; R³ is hydrogen; R⁴ is tert-butyl; R⁵ is selected fromthe group consisting of hydroxy and methoxy; R^(A) is hydrogen; R^(B) ishydrogen; and R⁶ is phenyl substituted with one or two substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K).
 56. The compound or salt of claim 1,wherein:

is double carbon-carbon bond; R¹ is selected from the group consistingof hydrogen and methyl; R² is selected from the group consisting ofhydrogen, methyl, and halo; R³ is selected from the group consisting ofhydrogen and methyl; R⁴ is tert-butyl; R⁵ is selected from the groupconsisting of hydrogen, hydroxy, methoxy, and halo; and R⁶ is phenylsubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).
 57. The compound orsalt of claim 1, wherein:

is double carbon-carbon bond; R¹ is hydrogen; R² is hydrogen; R³ ishydrogen; R⁴ is tert-butyl; R⁵ is methoxy; and R⁶ is phenyl substitutedwith one or two substituents independently selected from the groupconsisting of R^(E), R^(F), R^(I), R^(J), and R^(K).
 58. The compound orsalt of claim 1, wherein:

is double carbon-carbon bond; R¹ is hydrogen; R² is hydrogen; R³ ishydrogen; R⁴ is tert-butyl; R⁵ is methoxy; and R⁶ is phenyl substitutedwith R^(J).
 59. The compound or salt of claim 1, wherein: R¹ is selectedfrom the group consisting of hydrogen and methyl; R² is selected fromthe group consisting of hydrogen, methyl, and halo; R³ is selected fromthe group consisting of hydrogen and methyl; R⁴ is selected from thegroup consisting of C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-memberedheterocyclyl, wherein: (a) the C₁-C₄-alkyl optionally is substitutedwith up to three substituents independently selected from the groupconsisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and (b)the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally aresubstituted with one or two substituents independently selected from thegroup consisting of alkyl, halo, and alkylsulfonylamino; R⁵ is selectedfrom the group consisting of hydrogen, hydroxy, alkyloxy, and halo; oneof R^(A) and R^(B) is hydrogen, and the other is selected from the groupconsisting of hydrogen, methyl, methoxy, and halo; R⁶ is selected fromthe group consisting of C₅-C₆-carbocyclyl and 5-6-membered heterocyclyl,wherein each such substituent is substituted with one, two, threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K); each R^(E) isindependently selected from the group consisting of chloro, fluoro,nitro, hydroxy, oxo, carboxy, amino, imino, aldehydro, and alkylamino;each R^(F) is an independently selected alkyl optionally substitutedwith a substituent selected from the group consisting of carboxy, halo,amino, imino, and aminosulfonyl, wherein: the amino, imino, andaminosulfonyl optionally are substituted with one or two substituentsindependently selected from the group consisting of alkyl,alkylsulfonyl, and alkylsulfonylamino; each R^(I) is independentlyselected from the group consisting of alkylcarbonyl and aminocarbonyl,wherein: the aminocarbonyl optionally is substituted with a substituentselected from the group consisting of alkyl, alkyloxyalkyl,alkylsulfonyl, and alkylsulfonylamino; each R^(J) is independentlyselected from the group consisting of alkylsulfonylamino,alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino,wherein: (a) the amino portion of such substituents optionally issubstituted with a substituent independently selected from the groupconsisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy,aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl,wherein: (1) the carbocyclyl portion of the carbocyclylalkyl and theheterocyclyl portion of the heterocyclylalkyl optionally are substitutedwith one or two substituents independently selected from the groupconsisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano,oxo, and amino, and (2) the amino portion of the aminocarbonylalkyloptionally is substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkenyl, and alkynyl, (b)the alkyl, alkenyl, and alkynyl portion of such substituents optionallyis substituted with one or two substituents independently selected fromthe group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl,alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, andcyano, wherein: the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyland alkyloxy, wherein: the alkyl optionally is substituted with one ormore hydroxy; and each R^(K) is independently selected from the groupconsisting of aminosulfonyl and alkylsulfonyl, wherein: (a) thealkylsulfonyl optionally is substituted with one or two substituentsindependently selected from the group consisting of carboxy, hydroxy,halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl,alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, andaminocarbonyl; and (b) the aminosulfonyl optionally is substituted withone or two substituents independently selected alkyl.
 60. A compound orsalt thereof, wherein the compound is selected from the group ofcompounds shown in Tables 1-7. 61.(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidecrystalline form selected from the group consisting of: crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedisodium salt nonahydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6-0.2, 12.9±0.2, 14.7±0.2, 16.4±0.2,17.8±0.2, 19.4±0.2, 19.8±0.2, 20.8±0.2, 21.9±0.2, and 23.5±0.2 degrees2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedisodium salt nonahydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of4.3±0.2, 10.4±0.2, 10.9±0.2, 11.6±0.2, 12.9±0.2, 14.7±0.2, 14.9±0.2,16.4±0.2, 17.8±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2, 20.8±0.2, 20.9±0.2,21.9±0.2, 22.1±0.2, and 23.5±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedisodium salt nonahydrate having an X-ray powder diffraction patternsubstantially as shown in FIG. 1; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidenonahydrate disodium salt having cell unit parameters, wherein a is 8.9Å, b is 9.4 Å, and c is 20.7 Å; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedisodium salt tetrahydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of4.8±0.2, 12.1±0.2, 14.0±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2, 21.6±0.2,25.0±0.2, and 29.5±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedisodium salt tetrahydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of4.8±0.2, 12.1±0.2, 14.0±0.2, 14.4±0.2, 17.0±0.2, 17.5±0.2, 20.9±0.2,21.6±0.2, 25.0±0.2, 29.5±0.2, and 34.2±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedisodium salt tetrahydrate having an X-ray powder diffraction patternsubstantially as shown in FIG. 2; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedipotassium salt tetrahydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of5.0±0.2, 11.9±0.2, 12.4±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2, 17.1±0.2,20.8±0.2, 21.3±0.2, 22.2±0.2, 24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedipotassium salt tetrahydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of5.0±0.2, 11.9±0.2, 12.4±0.2, 12.6±0.2, 13.7±0.2, 15.0±0.2, 16.5±0.2,16.7±0.2, 17.1±0.2, 20.7±0.2, 20.8±0.2, 21.3±0.2, 22.2±0.2, 22.4±0.2,24.0±0.2, 26.4±0.2, and 29.3±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide dipotassium salt tetrahydrate having an X-raypowder diffraction pattern substantially as shown in FIG. 4; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidedipotassium salt tetrahydrate having unit cell parameters, wherein a is14.5 Å, b is 10.8 Å, and c is 35.8 Å; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt trihydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2,21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt trihydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 13.6±0.2, 15.3±0.2, 16.9±0.2,21.2±0.2, 21.7±0.2, 21.7±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, and 23.0±0.2degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt trihydrate having an X-ray powder diffraction patterncomprising five or more peaks selected from the group consisting of4.8±0.2, 10.8±0.2, 11.3±0.2, 13.4±0.2, 15.3±0.2, 16.9±0.2, 21.2±0.2,21.7±0.2, 22.1±0.2, 22.5±0.2, and 23.0±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt trihydrate having unit cell parameters, wherein a is9.0 Å, b is 8.3 Å, and c is 18.6 Å; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt dihydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of7.7±0.2, 8.8±0.2, 16.1±0.2, and 19.7±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt dihydrate having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of7.7±0.2, 8.8±0.2, 12.4±0.2, 14.0±0.2, 16.1±0.2, 17.7±0.2, 19.2±0.2,19.7±0.2, 23.1±0.2, and 29.2±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonopotassium salt dihydrate having an X-ray powder diffraction patternsubstantially as shown in FIG. 6; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide1/7 potassium salt having an X-ray powder diffraction pattern comprisingone or more peaks selected from the group consisting of 7.7±0.2,8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2,16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2,20.2±0.2, 20.5±0.2, 21.2±0.2, 22.1±0.2, and 22.9±0.2 degrees 2θ;crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide1/7 potassium salt having an X-ray powder diffraction pattern comprisingone or more peaks selected from the group consisting of 7.7±0.2,8.3±0.2, 10.1±0.2, 10.6±0.2, 11.4±0.2, 12.0±0.2, 13.4±0.2, 15.6±0.2,16.3±0.2, 16.7±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 19.9±0.2,20.2±0.2, 20.5±0.2, 20.8±0.2, 21.2±0.2, 22.1±0.2, 22.9±0.2, 24.3±0.2,24.9±0.2, and 25.1±0.2 degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide1/7 potassium salt having an X-ray powder diffraction patternsubstantially as shown in FIG. 8; crystalline(E-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonodiethylamine salt tetrahydrate having an X-ray powder diffractionpattern comprising one or more peaks selected from the group consistingof 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2,19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, and 29.8±0.2 degrees 2θ;crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonodiethylamine salt tetrahydrate having an X-ray powder diffractionpattern comprising one or more peaks selected from the group consistingof 9.5±0.2, 10.0±0.2, 11.8±0.2, 12.1±0.2, 14.4±0.2, 16.8±0.2, 17.6±0.2,19.4±0.2, 19.8±0.2, 20.8±0.2, 21.4±0.2, 21.8±0.2, 21.9±0.2, and 29.8±0.2degrees 2θ; crystalline(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidemonodiethylamine salt tetrahydrate having an X-ray powder diffractionpattern substantially as shown in FIG. 9; crystalline pattern A(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern comprising one or more peaksselected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2,12.4±0.2, 14.5±0.2, 18.8±0.2, 22.7±0.2, and 29.2±0.2 degrees 2θ;crystalline pattern A(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern comprising one or more peaksselected from the group consisting of 5.8±0.2, 9.9±0.2, 11.8±0.2,12.4±0.2, 14.0±0.2, 14.5±0.2, 15.3±0.2, 18.5±0.2, 18.8±0.2, 22.2±0.2,22.7±0.2, 23.8±0.2, 26.0±0.2, and 29.2±0.2 degrees 2θ; crystallinepattern A(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern substantially as shown inFIG. 11; crystalline pattern B(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern comprising one or more peaksselected from the group consisting of 11.5±0.2, 13.3±0.2, 15.4±0.2,16.4±0.2, 17.1±0.2, 18.6±0.2, 19.4±0.2, 20.4±0.2, 21.6±0.2, 22.4±0.2,24.0±0.2, 26.8±0.2, and 29.0±0.2 degrees 2θ; crystalline pattern B(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern substantially as shown inFIG. 13; crystalline pattern C(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern comprising one or more peaksselected from the group consisting of 7.7±0.2, 10.1±0.2, 10.6±0.2,12.0±0.2, 13.4±0.2, 16.2±0.2, 19.4±0.2, 20.5±0.2, 21.4±0.2, 22.0±0.2,22.6±0.2, 24.3±0.2, and 27.6±0.2 degrees 2θ; crystalline pattern C(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern substantially as shown inFIG. 14; crystalline pattern D(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern comprising one or more peaksselected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2,15.2±0.2, 16.1±0.2, 16.9±0.2, 19.9±0.2, 22.1±0.2, 24.7±0.2, and 26.0±0.2degrees 2θ; crystalline pattern D(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern comprising one or more peaksselected from the group consisting of 5.8±0.2, 10.7±0.2, 11.2±0.2,15.2±0.2, 16.1±0.2, 16.9±0.2, 17.1±0.2, 19.9±0.2, 20.1±0.2, 22.1±0.2,24.7±0.2, and 26.0±0.2 degrees 2θ; crystalline pattern D(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehaving an X-ray powder diffraction pattern substantially as shown inFIG. 15; crystalline pattern A(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 5.1±0.2, 7.9±0.2,9.5±0.2, 10.3±0.2, 13.7±0.2, 16.5±0.2, 17.1±0.2, 17.5±0.2, 18.8±0.2,19.2±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2, 25.8±0.2, 26.8±0.2, and 28.4±0.2degrees 2θ; crystalline pattern A(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern substantially asshown in FIG. 16; crystalline pattern A(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 6.3±0.2, 7.7±0.2,10.4±0.2, 12.7±0.2, 13.3±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2,18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2, 26.8±0.2, and 29.0±0.2degrees 2θ; crystalline pattern B(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 6.3±0.2, 7.7±0.2,10.4±0.2, 12.7±0.2, 13.3±0.2, 13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2,18.5±0.2, 18.6±0.2, 18.9±0.2, 19.4±0.2, 22.5±0.2, 23.5±0.2, 24.0±0.2,26.8±0.2, and 29.0±0.2 degrees 2θ; crystalline pattern B(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern substantially asshown in FIG. 18; crystalline pattern C(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 10.5±0.2, 13.3±0.2,14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2, 22.5±0.2,23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2θ; crystalline pattern C(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 10.5±0.2, 13.3±0.2,13.5±0.2, 14.9±0.2, 15.4±0.2, 16.4±0.2, 18.6±0.2, 19.0±0.2, 19.4±0.2,22.5±0.2, 23.5±0.2, 26.9±0.2, and 29.0±0.2 degrees 2θ; crystallinepattern C(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern substantially asshown in FIG. 20; crystalline pattern D(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 6.6±0.2, 10.0±±0.2,10.5±0.2, 11.1±0.2, 11.6±0.2, 12.2±0.2, 14.2±0.2, 16.6±0.2, 17.1±0.2,17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2, 23.1±0.2,23.6±0.2, 24.6±0.2, 25.2±0.2, 27.2±0.2, 29.1±0.2, and 31.0±0.2 degrees2θ; crystalline pattern D(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 6.6±0.2, 10.0±0.2,10.5±0.2, 11.1±0.2, 11.6±0.2, 12.2±0.2, 12.5±0.2, 14.2±0.2, 16.6±0.2,17.1±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 21.4±0.2, 22.7±0.2,22.8±0.2, 23.1±0.2, 23.6±0.2, 24.6±0.2, 24.9±0.2, 25.2±0.2, 27.2±0.2,29.1±0.2, and 31.0±0.2 degrees 2θ; crystalline pattern D(E-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern substantially asshown in FIG. 22; crystalline pattern D(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having unit cell parameters, wherein a is 17.8 Å, b is 9.6 Å,and c is 27.0 Å; crystalline pattern E(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 6.2±0.2, 7.8±0.2,10.2±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2, 21.8±0.2,24.5±0.2, and 28.0±0.2 degrees 2θ; crystalline pattern E(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern comprising one ormore peaks selected from the group consisting of 6.2±0.2, 7.8±0.2,10.2±0.2, 10.4±0.2, 10.7±0.2, 12.1±0.2, 16.3±0.2, 19.7±0.2, 20.9±0.2,21.8±0.2, 24.5±0.2, and 28.0±0.2 degrees 2θ; crystalline pattern E(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having an X-ray powder diffraction pattern substantially asshown in FIG. 23; and crystalline pattern E(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamidehydrate having unit cell parameters, wherein a is 9.5 Å, b is 14.5 Å,and c is 17.3 Å.
 62. A pharmaceutical composition comprising one or morecompounds and/or salts recited in claim 1 and one or more excipients.63. The pharmaceutical composition of claim 62, wherein thepharmaceutical composition further comprises one or more additionaltherapeutic agents.
 64. A method for inhibiting replication of aribonucleic acid (RNA) virus, wherein the method comprises exposing thevirus to one or more compounds and/or salts recited in claim
 1. 65. Themethod of claim 64, wherein the RNA virus is hepatitis C virus (HCV).66. A method for treating hepatitis C in a mammal in need of suchtreatment, wherein the method comprises administering to the mammal oneor more compounds and/or salts recited in claim
 1. 67. The method ofclaim 66, wherein the mammal is human.
 68. The method of claim 66,wherein the method further comprises administering to the mammal one ormore additional therapeutic agents.
 69. The method of claim 68, whereinone or more additional therapeutic agents are selected from the groupconsisting of interferon agent, ribavirin, HCV inhibitor, and HIVinhibitor.
 70. A pharmaceutical composition comprising one or morecrystalline forms recited in claim 61 and one or more excipients. 71.The pharmaceutical composition of claim 70, wherein the pharmaceuticalcomposition further comprises one or more additional therapeutic agents.72. A method for inhibiting replication of a ribonucleic acid (RNA)virus, wherein the method comprises exposing the virus to one or morecrystalline forms recited in claim in claim
 61. 73. The method of claim72, wherein the RNA virus is hepatitis C virus (HCV).
 74. A method fortreating hepatitis C in a mammal in need of such treatment, wherein themethod comprises administering to the mammal one or more crystallineforms recited in claim
 61. 75. The method of claim 74, wherein themammal is human.
 76. The method of claim 74, wherein the method furthercomprises administering to the mammal one or more additional therapeuticagents.
 77. The method of claim 76, wherein one or more additionaltherapeutic agents are selected from the group consisting of interferonagent, ribavirin, HCV inhibitor, and HIV inhibitor. 78-83. (canceled)